2024/02/20 更新

写真a

アリムラ タクロウ
有村 卓朗
ARIMURA Takuro
所属
農水産獣医学域獣医学系 共同獣医学部 獣医学科 教授
職名
教授
外部リンク

学位

  • 博士(医学) ( 2001年3月   東京医科歯科大学 )

研究キーワード

  • 難治性循環器疾患(特発性心筋症及び不整脈)

  • 遺伝子変異

  • 心疾患モデル動物

研究分野

  • ライフサイエンス / 遺伝学

  • ライフサイエンス / 循環器内科学

学歴

  • 東京医科歯科大学   大学院 医学系研究科

    1997年 - 2001年

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    国名: 日本国

  • 東京農工大学   農学部   獣医学科

    1991年 - 1997年

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    国名: 日本国

経歴

  • 鹿児島大学   農水産獣医学域獣医学系 共同獣医学部 獣医学科   教授

    2020年 - 現在

  • 鹿児島大学   農水産獣医学域獣医学系 共同獣医学部 獣医学科   准教授

    2016年 - 2020年

  • 鹿児島大学   農水産獣医学域獣医学系 共同獣医学部 獣医学科   特任准教授

    2013年 - 2016年

  • 東京医科歯科大学   難治疾患研究所 分子病態分野   准教授

    2012年 - 2013年

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    国名:日本国

  • 東京医科歯科大学   難治疾患研究所 分子病態分野   助教

    2007年 - 2012年

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    国名:日本国

  • 東京医科歯科大学   難治疾患研究所 分子病態分野   助手

    2005年 - 2007年

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    国名:日本国

  • フランス国立保健医学研究所(INSERM)   UR582(横紋筋疾患研究治療分野)   研究員

    2002年 - 2004年

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    国名:フランス共和国

  • 国立医薬品食品衛生研究所   病理部   研究員

    2001年 - 2002年

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    国名:日本国

  • 日本学術振興会   特別研究員

    2000年 - 2001年

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    国名:日本国

▼全件表示

所属学協会

  • 日本循環器学会

    2015年 - 現在

  • International Society for Heart Research

    2015年 - 現在

  • 日本人類遺伝学会

    2015年 - 現在

  • 日本分子生物学会

    2015年 - 現在

  • World Muscle Society

    2015年 - 現在

  • 日本獣医学会

    2015年 - 現在

▼全件表示

委員歴

  • 欧州獣医学教育機関協会 (EAEVE)   欧州獣医学教育評価システム (ESEVT) 評価専門員  

    2023年 - 現在   

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    団体区分:学協会

留学歴

  • 2002年 - 2004年   フランス国立保健医学研究所  

取得資格

  • 獣医師

 

論文

  • Enomoto H., Mittal N., Inomata T., Arimura T., Izumi T., Kimura A., Fukuda K., Makino S. .  Dilated cardiomyopathy-linked heat shock protein family D member 1 mutations cause up-regulation of reactive oxygen species and autophagy through mitochondrial dysfunction .  Cardiovascular Research117 ( 4 ) 1118 - 1131   2021年3月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cardiovascular Research  

    Aims: During heart failure, the levels of circulatory heat shock protein family D member 1 (HSP60) increase. However, its underlying mechanism is still unknown. The apical domain of heat shock protein family D member 1 (HSPD1) is conserved throughout evolution. We found a point mutation in HSPD1 in a familial dilated cardiomyopathy (DCM) patient. A similar point mutation in HSPD1 in the zebrafish mutant, nbl, led to loss of its regenerative capacity and development of pericardial oedema under heat stress condition. In this study, we aimed to determine the direct involvement of HSPD1 in the development of DCM. Methods and results: By Sanger method, we found a point mutation (Thr320Ala) in the apical domain of HSPD1, in one familial DCM patient, which was four amino acids away from the point mutation (Val324Glu) in the nbl mutant zebrafish. The nbl mutants showed atrio-ventricular block and sudden death at 8-month post-fertilization. Histological and microscopic analysis of the nbl mutant hearts showed decreased ventricular wall thickness, elevated level of reactive oxygen species (ROS), increased fibrosis, mitochondrial damage, and increased autophagosomes. mRNA and protein expression of autophagy-related genes significantly increased in nbl mutants. We established HEK293 stable cell lines of wild-type, nbl-type, and DCM-type HSPD1, with tetracycline-dependent expression. Compared to wild-type, both nbl-and DCM-type cells showed decreased cell growth, increased expression of ROS and autophagy-related genes, inhibition of the activity of mitochondrial electron transport chain complexes III and IV, and decreased mitochondrial fission and fusion. Conclusion: Mutations in HSPD1 caused mitochondrial dysfunction and induced mitophagy. Mitochondrial dysfunction caused increased ROS and cardiac atrophy.

    DOI: 10.1093/cvr/cvaa158

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  • Higashikuse Y., Mittal N., Arimura T., Yoon S.H., Oda M., Enomoto H., Kaneda R., Hattori F., Suzuki T., Kawakami A., Gasch A., Furukawa T., Labeit S., Fukuda K., Kimura A., Makino S. .  Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients .  DMM Disease Models and Mechanisms12 ( 11 )   2019年11月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:DMM Disease Models and Mechanisms  

    Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascularmutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M-line disassembly that is similar to the pathological changes found in HCM. Positional cloning revealed a missense mutation in an immunoglobulin (Ig) domain located in the Mline-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. In vitro studies revealed that the mutations found both in medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

    DOI: 10.1242/dmm.041103

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  • Arimura T., Muchir A., Kuwahara M., Morimoto S., Ishikawa T., Du C.K., Zhan D.Y., Nakao S., Machida N., Tanaka R., Yamane Y., Hayashi T., Kimura A. .  Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance .  American Journal of Physiology - Heart and Circulatory Physiology314 ( 6 ) H1192-H1202 - H1202   2018年6月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Journal of Physiology - Heart and Circulatory Physiology  

    Mutations in genes encoding components of the sarcomere cause cardiomyopathy, which is often associated with abnormal Ca2+ sensitivity of muscle contraction. We have previously shown that a heartspecific myosin light chain phosphatase small subunit (hHS-M21) increases the Ca2+ sensitivity of muscle contraction. The aim of the present study was to investigate the function of hHS-M21 in vivo and the causative role of abnormal Ca2+ sensitivity in cardiomyopathy. We generated transgenic mice with cardiac-specific overexpression of hHS-M21. We confirmed that hHS-M21 increased the Ca2+ sensitivity of cardiac muscle contraction in vivo, which was not followed by an increased phosphorylation of myosin light chain 2 isoforms. hHS-M21 transgenic mice developed severe systolic dysfunction with myocardial fibrosis and degeneration of cardiomyocytes in association with sinus bradycardia and atrioventricular conduction defect. The contractile dysfunction and cardiac fibrosis were improved by treatment with the Rho kinase inhibitor fasudil. Our findings suggested that the overexpression of hHS-M21 results in cardiac dysfunction and conduction disturbance via non-myosin light chain 2 phosphorylationdependent regulation. NEW & NOTEWORTHY The present study is the first to develop mice with transgenic overexpression of a heart-specific myosin light chain phosphatase small subunit (hHS-M21) and to examine the effects of hHS-M21 on cardiac function. Elevation of hHS-M21 induced heart failure with myocardial fibrosis and degeneration of cardiomyocytes accompanied by supraventricular arrhythmias.

    DOI: 10.1152/ajpheart.00696.2017

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  • Kawai H., Morimoto S., Takakuwa Y., Ueda A., Inada K., Sarai M., Arimura T., Mutoh T., Kimura A., Ozaki Y. .  Hypertrophic cardiomyopathy accompanied by spinocerebellar atrophy with a novel mutation in troponin i gene .  International Heart Journal57 ( 4 ) 507 - 10   2016年7月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Heart Journal  

    We report the case of a 66 year-old woman with chronic atrial fibrillation, hypertrophic cardiomyopathy (HCM), and spinocerebellar atrophy (SCA). Her mother and first-born son had died of heart disease at the ages of 65 and 16 years, respectively. Four of her 8 siblings had died suddenly of unknown cause or of heart disease, and 2 others of cerebral infarction by the 7th decade. Genetic testing revealed that she had a novel mutation (c. 482C > A, p. Ala161Asp) in the troponin I gene (TNNI3), and no abnormality of the GAA repeat in the frataxin gene. Her older brother with SCA but without HCM was also analyzed, with no abnormality noted in either gene. The Ala161Asp mutation in TNNI3 was implicated in the pathogenesis of her HCM, though an association between HCM and SCA was not revealed.

    DOI: 10.1536/ihj.15-444

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J04789&link_issn=&doc_id=20160803160021&doc_link_id=10.1536%2Fihj.15-444&url=https%3A%2F%2Fdoi.org%2F10.1536%2Fihj.15-444&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Koizumi A., Sasano T., Kimura W., Miyamoto Y., Aiba T., Ishikawa T., Nogami A., Fukamizu S., Sakurada H., Takahashi Y., Nakamura H., Ishikura T., Koseki H., Arimura T., Kimura A., Hirao K., Isobe M., Shimizu W., Miura N., Furukawa T. .  Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias .  European Heart Journal37 ( 18 ) 1469 - 75   2016年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Heart Journal  

    Aim Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. Methods and results Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. Conclusion IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.

    DOI: 10.1093/eurheartj/ehv449

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  • Kadota C., Arimura T., Hayashi T., Naruse T.K., Kawai S., Kimura A. .  Screening of sarcomere gene mutations in young athletes with abnormal findings in electrocardiography: Identification of a MYH7 mutation and MYBPC3 mutations .  Journal of Human Genetics60 ( 10 ) 641 - 5   2015年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Human Genetics  

    There is an overlap between the physiological cardiac remodeling associated with training in athletes, the so-called athlete's heart, and mild forms of hypertrophic cardiomyopathy (HCM), the most common hereditary cardiac disease. HCM is often accompanied by unfavorable outcomes including a sudden cardiac death in the adolescents. Because one of the initial signs of HCM is abnormality in electrocardiogram (ECG), athletes may need to monitor for ECG findings to prevent any unfavorable outcomes. HCM is caused by mutations in genes for sarcomere proteins, but there is no report on the systematic screening of gene mutations in athletes. One hundred and two genetically unrelated young Japanese athletes with abnormal ECG findings were the subjects for the analysis of four sarcomere genes, MYH7, MYBPC3, TNNT2 and TNNI3. We found that 5 out of 102 (4.9%) athletes carried mutations: a heterozygous MYH7 Glu935Lys mutation, a heterozygous MYBPC3 Arg160Trp mutation and another heterozygous MYBPC3 Thr1046Met mutation, all of which had been reported as HCM-associated mutations, in 1, 2 and 2 subjects, respectively. This is the first study of systematic screening of sarcomere gene mutations in a cohort of athletes with abnormal ECG, demonstrating the presence of sarcomere gene mutations in the athlete's heart.

    DOI: 10.1038/jhg.2015.81

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    その他リンク: http://search.jamas.or.jp/link/ui/2016231641

  • Ishikawa Taisuke, Jou Chuanchau J., Nogami Akihiko, Kowase Shinya, Arrington Cammon B., Barnett Spencer M., Harrell Daniel T., Arimura Takuro, Tsuji Yukiomi, Kimura Akinori, Makita Naomasa .  Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome .  Circulation: Arrhythmia and Electrophysiology8 ( 2 ) 400 - 8   2015年4月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Heart Association Inc.  

    Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown. Methods and Results-We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in MYH6 and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human α-MHC but not by delE933 α-MHC. Conclusions-The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome.

    DOI: 10.1161/CIRCEP.114.002534

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  • Tanaka A., Yuasa S., Mearini G., Egashira T., Seki T., Kodaira M., Kusumoto D., Kuroda Y., Okata S., Suzuki T., Inohara T., Arimura T., Makino S., Kimura K., Kimura A., Furukawa T., Carrier L., Node K., Fukuda K. .  Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes .  Journal of the American Heart Association3 ( 6 ) e001263   2014年11月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American Heart Association  

    Background-Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. Methods and Results-We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. Conclusions-Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

    DOI: 10.1161/JAHA.114.001263

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  • Seigo Okada, Yasuo Suzuki, Takuro Arimura, Akinori Kimura, Hiroko Narumi, Shunji Hasegawa .  A novel de novo mutation of β-cardiac myosin heavy chain gene found in a twelve-year-old boy with hypertrophic cardiomyopathy. .  Journal of genetics93 ( 2 ) 557 - 60   2014年8月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • An J., Nakajima T., Shibata H., Arimura T., Yasunami M., Kimura A. .  A novel link of HLA locus to the regulation of immunity and infection: NFKBIL1 regulates alternative splicing of human immune-related genes and influenza virus M gene .  Journal of Autoimmunity47   25 - 33   2013年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Autoimmunity  

    HLA locus contains immune-related genes and genetically regulates immune responses against both foreign- and self-antigens in humans. Inhibitor of κB-like protein (IκBL), encoded by HLA-linked NFKBIL1, is a protein of unknown function, while genetic variations in NFKBIL1 are known to associate with the susceptibility to inflammatory and/or autoimmune diseases. In this study, we found that IκBL suppressed exon exclusion in alternative splicing of human immune-related genes such as CD45. Yeast-two-hybrid screening and immunoprecipitation assay revealed molecular association of IκBL with CLK1, a serine/threonine and tyrosine kinase, which plays a role in the alternative splicing. Unexpectedly, we found that the regulation of alternative splicing in CD45 by IκBL was independent from the kinase activity of CLK1. On the other hand, it was demonstrated that an SR protein, ASF/SF2, bound both IκBL and CLK1 at the RNA-recognition motifs of ASF/SF2, implying a competition of IκBL and CLK1 on SR protein. In addition, IκBL was found to regulate the CLK1-dependent synthesis of M2 RNA, a splice variant of influenza A virus M gene. These observations suggest a functional involvement of IκBL in the regulation of alternative splicing in both human and viral genes, which is a novel link of HLA locus to the regulation of immunity and infection in humans. © 2013 Elsevier Ltd.

    DOI: 10.1016/j.jaut.2013.07.010

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  • Arimura T., Onoue K., Takahashi-Tanaka Y., Ishikawa T., Kuwahara M., Setou M., Shigenobu S., Yamaguchi K., Bertrand A.T., Machida N., Takayama K., Fukusato M., Tanaka R., Somekawa S., Nakano T., Yamane Y., Kuba K., Imai Y., Saito Y., Bonne G., Kimura A. .  Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations .  Cardiovascular Research99 ( 3 ) 382 - 94   2013年8月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cardiovascular Research  

    Aims Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM. Methods and results A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples fromthe LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice. Conclusion These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.

    DOI: 10.1093/cvr/cvt106

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  • Crocini C., Arimura T., Reischmann S., Eder A., Braren I., Hansen A., Eschenhagen T., Kimura A., Carrier L. .  Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue .  Basic Research in Cardiology108 ( 3 ) 349 - 349   2013年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Basic Research in Cardiology  

    Hypertrophic cardiomyopathy (HCM) is a myocardial disease associated with mutations in sarcomeric genes. Three mutations were found in ANKRD1, encoding ankyrin repeat domain 1 (ANKRD1), a transcriptional co-factor located in the sarcomere. In the present study, we investigated whether expression of HCM-associated ANKRD1 mutations affects contraction parameters after gene transfer in engineered heart tissues (EHTs). EHTs were generated from neonatal rat heart cells and were transduced with adeno-associated virus encoding GFP or myc-tagged wild-type (WT) or mutant (P52A, T123M, or I280V) ANKRD1. Contraction parameters were analyzed from day 8 to day 16 of culture, and evaluated in the absence or presence of the proteasome inhibitor epoxomicin for 24 h. Under standard conditions, only WT- and T123M-ANKRD1 were correctly incorporated in the sarcomere. T123M-ANKRD1-transduced EHTs exhibited higher force and velocities of contraction and relaxation than WT- P52A- and I280V-ANKRD1 were highly unstable, not incorporated into the sarcomere, and did not induce contractile alterations. After epoxomicin treatment, P52A and I280V were both stabilized and incorporated into the sarcomere. I280V-transduced EHTs showed prolonged relaxation. These data suggest different impacts of ANKRD1 mutations on cardiomyocyte function: gain-of-function for T123M mutation under all conditions and dominant-negative effect for the I280V mutation which may come into play only when the proteasome is impaired. © 2013 Springer-Verlag Berlin Heidelberg.

    DOI: 10.1007/s00395-013-0349-x

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  • Ishikawa T., Takahashi N., Ohno S., Sakurada H., Nakamura K., On Y.K., Park J.E., Makiyama T., Horie M., Arimura T., Makita N., Kimura A. .  Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5 .  Circulation Journal77 ( 4 ) 959 - 67   2013年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Journal  

    Background: Brugada syndrome (BrS) is characterized by specific alterations on ECG in the right precordial leads and associated with ventricular arrhythmia that may manifest as syncope or sudden cardiac death. The major causes of BrS are mutations in SCN5A for a large subunit of the sodium channel, Nav1.5, but a mutation in SCN3B for a small subunit of sodium channel, Navβ3, has been recently reported in an American patient. Methods and Results: A total of 181 unrelated BrS patients, 178 Japanese and 3 Koreans, who had no mutations in SCN5A, were examined for mutations in SCN3B by direct sequencing of all exons and adjacent introns. A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls. The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells. Whole-cell patch clamp recordings of the transfected cells revealed that the sodium currents were significantly reduced by the SCN3B mutation. Conclusions: The Val110Ile mutation of SCN3B is a relatively common cause of SCN5A-negative BrS in Japan, which has a reduced sodium current because of the loss of cell surface expression of Nav1.5.

    DOI: 10.1253/circj.CJ-12-0995

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  • Arimura T., Takeya R., Ishikawa T., Yamano T., Matsuo A., Tatsumi T., Nomura T., Sumimoto H., Kimura A. .  Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor .  Circulation Journal77 ( 12 ) 2990 - 6   2013年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Journal  

    Background: Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. Methods and Results: We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3. Conclusions: The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.

    DOI: 10.1253/circj.CJ-13-0255

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  • Ishikawa T., Sato A., Marcou C.A., Tester D.J., Ackerman M.J., Crotti L., Schwartz P.J., On Y.K., Park J.E., Nakamura K., Hiraoka M., Nakazawa K., Sakurada H., Arimura T., Makita N., Kimura A. .  A novel disease gene for Brugada syndrome: Sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5 .  Circulation: Arrhythmia and Electrophysiology5 ( 6 ) 1098 - 107   2012年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation: Arrhythmia and Electrophysiology  

    Background: Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. Methods and Results: We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. Conclusions: The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel. © 2012 American Heart Association, Inc.

    DOI: 10.1161/CIRCEP.111.969972

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  • Purevjav E., Arimura T., Augustin S., Huby A.C., Takagi K., Nunoda S., Kearney D.L., Taylor M.D., Terasaki F., Bos J.M., Ommen S.R., Shibata H., Takahashi M., Itoh-satoh M., Mckenna W.J., Murphy R.T., Labeit S., Yamanaka Y., Machida N., Park J.E., Alexander P.M.A., Weintraub R.G., Kitaura Y., Ackerman M.J., Kimura A., Towbin J.A. .  Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations .  Human Molecular Genetics21 ( 9 ) 2039 - 53   2012年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Molecular Genetics  

    Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN Q529X. Cardiac-restricted MYPN Y20C Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc. © The Author 2012. Published by Oxford University Press. All rights reserved.

    DOI: 10.1093/hmg/dds022

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  • Bertrand A.T., Renou L., Papadopoulos A., Beuvin M., Lacène E., Massart C., Ottolenghi C., Decostre V., Maron S., Schlossarek S., Cattin M.E., Carrier L., Malissen M., Arimura T., Bonne G. .  DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death .  Human Molecular Genetics21 ( 5 ) 1037 - 48   2012年3月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Molecular Genetics  

    The LMNA gene encodes lamin A/C intermediate filaments that polymerize beneath the nuclear membrane, and are also found in the nucleoplasm in an uncharacterized assembly state. They are thought to have structural functions and regulatory roles in signaling pathways via interaction with transcription factors. Mutations in LMNA have been involved in numerous inherited human diseases, including severe congenital muscular dystrophy (L-CMD). We created the Lmna δK32 knock-in mouse harboring a L-CMD mutation. Lmna δK32/δK32 mice exhibited striated muscle maturation delay and metabolic defects, including reduced adipose tissue and hypoglycemia leading to premature death. The level of mutant proteins was markedly lower in Lmna δK32/δK32, and while wild-type lamin A/C proteins were progressively relocated from nucleoplasmic foci to the nuclear rim during embryonic development, mutant proteins were maintained in nucleoplasmic foci. In the liver and during adipocyte differentiation, expression of δK32-lamin A/C altered sterol regulatory element binding protein 1 (SREBP-1) transcriptional activities. Taken together, our results suggest that lamin A/C relocation at the nuclear lamina seems important for tissue maturation potentially by releasing its inhibitory function on transcriptional factors, including but not restricted to SREBP-1. And importantly, L-CMD patients should be investigated for putative metabolic disorders. © The Author 2011. Published by Oxford University Press. All rights reserved.

    DOI: 10.1093/hmg/ddr534

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  • Otsuka H., Arimura T., Abe T., Kawai H., Aizawa Y., Kubo T., Kitaoka H., Nakamura H., Nakamura K., Okamoto H., Ichida F., Ayusawa M., Nunoda S., Isobe M., Matsuzaki M., Doi Y.L., Fukuda K., Sasaoka T., Izumi T., Ashizawa N., Kimura A. .  Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy .  Circulation Journal76 ( 2 ) 453 - 61   2012年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Journal  

    Background: Hypertrophic cardiomyopathy (HCM), which is inherited as an autosomal dominant trait, is the most prevalent hereditary cardiac disease. Although there are several reports on the systematic screening of mutations in the disease-causing genes in European and American populations, only limited information is available for Asian populations, including Japanese. Methods and Results: Genetic screening of disease-associated mutations in 8 genes for sarcomeric proteins, MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC, was performed by direct sequencing in 112 unrelated Japanese proband patients with familial HCM; 37 different mutations, including 13 novel ones in 5 genes, MYH7, MYBPC3, TNNT2, TNNI3, and TPM1, were identified in 49 (43.8%) patients. Among them, 3 carried compound heterozygous mutations in MYBPC3 or TNNT2. The frequency of patients carrying the MYBPC3, MYH7, and TNNT2 mutations were 19.6%, 10.7%, and 8.9%, respectively, and the most frequently affected genes in the northeastern and southwestern parts of Japan were MYBPC3 and MYH7, respectively. Several mutations were found in multiple unrelated proband patients, for which the geographic distribution suggested founder effects of the mutations. Conclusions: This study demonstrated the frequency and distribution of mutations in a large cohort of familial HCM in Japan.

    DOI: 10.1253/circj.CJ-11-0876

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  • Akihiko Sato, Nobuo Sakamoto, Katsuya Ando, Takashi Kaneshiro, Hironori Uekita, Koichi Sugimoto, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Hitoshi Suzuki, Shu-ichi Saitoh, Masatomo Sato, Kazuaki Tamagawa, Takuro Arimura, Akinori Kimura, Yasuchika Takeishi .  Dilated phase of hypertrophic cardiomyopathy caused by two different sarcomere mutations, treated with surgical left ventricular reconstruction and cardiac resynchronization therapy with a defibrillator. .  Internal medicine (Tokyo, Japan)51 ( 18 ) 2559 - 64   2012年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein report the case of a 61-year-old woman with dilated phase of hypertrophic cardiomyopathy (D-HCM) who had been diagnosed with HCM 17 years previously. On admission, her left ventricle (LV) had marked dilation, dyssynchrony with diffuse severe hypokinesis, and ventricular tachycardia. She had two mutations in the cardiac myosin binding protein-C gene, which were suspected to be the causes of the D-HCM. We performed LV reconstruction surgery and cardiac resynchronization therapy with a defibrillator for her drug-resistant severe heart failure. After surgery, her New York Heart Association class dramatically improved, and she has not been re-hospitalized since these treatments.

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  • Arimura T., Ishikawa T., Nunoda S., Kawai S., Kimura A. .  Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes .  Human Mutation32 ( 12 ) 1481 - 91   2011年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Mutation  

    Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress. © 2011 Wiley Periodicals, Inc.

    DOI: 10.1002/humu.21603

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  • Kubo T., Kitaoka H., Okawa M., Baba Y., Hirota T., Hayato K., Yamasaki N., Matsumura Y., Otsuka H., Arimura T., Kimura A., Doi Y.L. .  Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy .  Circulation Journal75 ( 11 ) 2654 - 9   2011年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Journal  

    Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal-dominant pattern of inheritance mainly caused by single heterozygous mutations in sarcomere genes. Although multiple gene mutations have recently been reported in Western countries, clinical implications of multiple mutations in Japanese subjects are not clear. Methods and Results: A comprehensive genetic analysis of 5 sarcomere genes (cardiac β-myosin heavy chain gene [MYH7 ], cardiac myosin-binding protein C gene [MYBPC3], cardiac troponin T gene [TNNT2], α-tropomyosin gene [TPM1] and cardiac troponin I gene [TNNI3]) was performed in 93 unrelated patients and 14 mutations were identified in 28 patients. Twenty-six patients had single heterozygosity (20 in MYBPC3, 4 in MYH7, 1 in TNNT2, 1 in TNNI3), whereas 2 proband patients with familial HCM had double heterozygosity: 1 with P106fs in MYBPC3 and R869C in MYH7 and 1 with R945fs in MYBPC3 and E1049D in MYH7. From the results of the family survey and the previous literature on HCM mutations, P106fs, R945fs and R869C seemed to be pathological mutations and E1049D might be a rare polymorphism. The proband patient with P106fs and R869C double mutation was diagnosed as having HCM at an earlier age (28 years of age) than her relatives with single mutation, and had greater wall thickness with left ventricular outflow obstruction. Conclusions: One double mutation was identified in a Japanese cohort of HCM patients. Further studies are needed to clarify the clinical significance of multiple mutations including phenotypic severity.

    DOI: 10.1253/circj.CJ-10-1314

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  • Shichi D., Arimura T., Ishikawa T., Kimura A. .  Heart-specific small subunit of myosin light chain phosphatase activates rho-associated kinase and regulates phosphorylation of myosin phosphatase target subunit 1 .  Journal of Biological Chemistry285 ( 44 ) 33680 - 90   2010年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Biological Chemistry  

    Phosphorylation of myosin regulatory light chain (MLC) plays a regulatory role in muscle contraction, and the level of MLC phosphorylation is balanced by MLC kinase and MLC phosphatase (MLCP). MLCP consists of a catalytic subunit, a large subunit (MYPT1 or MYPT2), and a small subunit. MLCP activity is regulated by phosphorylation of MYPTs, whereas the role of small subunit in the regulation remains unknown. We previously characterized a human heart-specific small subunit (hHS-M21) that increased the sensitivity to Ca2+ in muscle contraction. In this study, we investigated the role of hHS-M 21 in the regulation of MLCP phosphorylation. Two isoforms of hHS-M21, hHS-M21A and hHS-M21B, preferentially bound the C-terminal one-third region of MYPT1 and MYPT2, respectively. Amino acid substitutions at a phosphorylation site of MYPT1, Ser-852, impaired the binding of MYPT1 and hHS-M21. The hHS-M21 increased the phosphorylation level of MYPT1 at Thr-696, which was attenuated by Rho-associated kinase (ROCK) inhibitors and small interfering RNAs for ROCK. In addition, hHS-M21 bound ROCK and enhanced the ROCK activity. These findings suggest that hHS-M21 is a heart-specific effector of ROCK and plays a regulatory role in the MYPT1 phosphorylation at Thr-696 by ROCK. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

    DOI: 10.1074/jbc.M110.122390

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  • Purevjav E., Varela J., Morgado M., Kearney D.L., Li H., Taylor M.D., Arimura T., Moncman C.L., McKenna W., Murphy R.T., Labeit S., Vatta M., Bowles N.E., Kimura A., Boriek A.M., Towbin J.A. .  Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis .  Journal of the American College of Cardiology56 ( 18 ) 1493 - 502   2010年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American College of Cardiology  

    Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM. © 2010 American College of Cardiology Foundation.

    DOI: 10.1016/j.jacc.2010.05.045

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  • Arimura T., Sato R., Machida N., Bando H., Zhan D., Morimoto S., Tanaka R., Yamane Y., Bonne G., Kimura A. .  Improvement of Left Ventricular Dysfunction and of Survival Prognosis of Dilated Cardiomyopathy by Administration of Calcium Sensitizer SCH00013 in a Mouse Model .  Journal of the American College of Cardiology55 ( 14 ) 1503 - 5   2010年4月査読 国際誌

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    記述言語:英語   出版者・発行元:Journal of the American College of Cardiology  

    DOI: 10.1016/j.jacc.2009.10.065

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  • Matuda S., Arimura T., Kimura A., Takekura H., Ohta S., Nakano K. .  A novel protein found in the I bands of myofibrils is produced by alternative splicing of the DLST gene .  Biochimica et Biophysica Acta - General Subjects1800 ( 1 ) 31 - 9   2010年1月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - General Subjects  

    Background: It is not known if the dihydrolipoamide succinyltransferase (DLST) gene, a mitochondrial protein, undergoes alternative splicing. We identified an uncharacterized protein reacting with an anti-DLST antibody in the I bands of myofibrils in rat skeletal muscle. Methods: Immunocytochemical staining with an anti-DLST antibody, the purification and amino acid sequence analysis of the protein, and the isolation and sequencing of the protein's cDNA were carried out to clarify the properties of the protein and its relationship to the DLST gene. Results: A pyrophosphate concentration >10 mM was necessary to extract the protein from myofibrils in the presence of salt with a higher concentration than 0.6 M, at an alkaline pH of 7.5-8.0. The protein corresponded to the amino acid sequence of the C-terminal side of DLST. The cDNAs for this protein were splicing variants of the DLST gene, with deletions of both exons 2 and 3, or only exon 2 or 3. These variants possessed an open reading frame from an initiation codon in exon 8 of the DLST gene to a termination codon in exon 15, generating a protein with a molecular weight of 30 kDa. Conclusions: The DLST gene undergoes alternative splicing, generating the protein isolated from the I bands of myofibrils. General significance: The DLST gene produces two different proteins with quite different functions via alternative splicing. © 2009.

    DOI: 10.1016/j.bbagen.2009.10.003

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  • Sato A., Arimura T., Makita N., Ishikawa T., Aizawa Y., Ushinohama H., Aizawa Y., Kimura A. .  Novel mechanisms of trafficking defect caused by KCNQ1 mutations found in long QT syndrome .  Journal of Biological Chemistry284 ( 50 ) 35122 - 33   2009年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Biological Chemistry  

    Long QT syndrome (LQTS) is a hereditary arrhythmia caused by mutations in genes for cardiac ion channels, including a potassium channel,KvLQT1.Inheritance of LQTS is usually autosomal-dominant, but autosomal-recessive inheritance can be observed in patients with LQTS accompanied by hearing loss. In this study, we investigated the functional alterations caused by KCNQ1 mutations, a deletion (delV595) and a frameshift (P631fs/19), which were identified in compound heterozygous state in two patients with autosomal-recessive LQTS not accompanied by hearing loss. Functional analyses showed that both mutations impaired cell surface expression due to trafficking defects. The mutations severely affected outward potassium currents without apparent dominant negative effects. It was found that delV595 impaired subunit binding, whereas P631fs/19 was retained in endoplasmic reticulum due to the newly added 19-amino acid sequence containing two retention motifs (R633GR and R646LR). This is the first report of novel mechanisms for trafficking abnormality of cardiac ion channels, providing us new insights into the molecular mechanisms of LQTS. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

    DOI: 10.1074/jbc.M109.017293

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  • Hinohara K., Nakajima T., Yasunami M., Houda S., Sasaoka T., Yamamoto K., Lee B.S., Shibata H., Tanaka-Takahashi Y., Takahashi M., Arimura T., Sato A., Naruse T., Ban J., Inoko H., Yamada Y., Sawabe M., Park J.E., Izumi T., Kimura A. .  Megakaryoblastic leukemia factor-1 gene in the susceptibility to coronary artery disease .  Human Genetics126 ( 4 ) 539 - 47   2009年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Genetics  

    Coronary artery disease (CAD) is based on the atherosclerosis of coronary artery and may manifest with myocardial infarction or angina pectoris. Although it is widely accepted that genetic factors are linked to CAD and several disease-related genes have been reported, only a few could be replicated suggesting that there might be some other CAD-related genes. To identify novel susceptibility loci for CAD, we used microsatellite markers in the screening and found six different candidate CAD loci. Subsequent single nucleotide polymorphism (SNP) association studies revealed an association between CAD and megakaryoblastic leukemia factor-1 gene (MKL1). The association with a promoter SNP of MKL1, -184C > T, was found in a Japanese population and the association was replicated in another Japanese population and a Korean population. Functional analysis of the MKL1 promoter SNP suggested that the higher MKL1 expression was associated with CAD. These findings suggest that MKL1 is involved in the pathogenesis of CAD. © Springer-Verlag 2009.

    DOI: 10.1007/s00439-009-0698-6

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  • Young-Eun Park, Yukiko K Hayashi, Gisèle Bonne, Takuro Arimura, Satoru Noguchi, Ikuya Nonaka, Ichizo Nishino .  Autophagic degradation of nuclear components in mammalian cells. .  Autophagy5 ( 6 ) 795 - 804   2009年8月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autophagy is an evolutionarily conserved intracellular mechanism for the degradation of organelles and proteins. Here we demonstrate the presence of perinuclear autophagosomes/autolysosomes containing nuclear components in nuclear envelopathies caused by mutations in the genes encoding A-type lamins (LMNA) and emerin (EMD). These autophagosomes/autolysosomes were sometimes bigger than a nucleus. The autophagic nature is further supported by upregulation of LC3-II in Lmna(H222P/H222P) fibroblasts. In addition, inhibition of autophagy led to the accumulation of nuclear abnormalities and reduced cell viability, strongly suggesting a beneficial role of autophagy, at least in these cells. Similar giant autophagosomes/autolysosomes were seen even in wild-type cells, albeit rarely, implying that this "nucleophagy" is not confined to the diseased condition, but may be seen even in physiologic conditions to clean up nuclear wastes produced by nuclear damage.

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  • Arimura T., Bos J.M., Sato A., Kubo T., Okamoto H., Nishi H., Harada H., Koga Y., Moulik M., Doi Y.L., Towbin J.A., Ackerman M.J., Kimura A. .  Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy .  Journal of the American College of Cardiology54 ( 4 ) 334 - 42   2009年7月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American College of Cardiology  

    Objectives: The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. Background: Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin. Methods: We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes. Results: Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes. Conclusions: CARP abnormalities may be involved in the pathogenesis of HCM. © 2009 American College of Cardiology Foundation.

    DOI: 10.1016/j.jacc.2008.12.082

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  • Moulik M., Vatta M., Witt S.H., Arola A.M., Murphy R.T., McKenna W.J., Boriek A.M., Oka K., Labeit S., Bowles N.E., Arimura T., Kimura A., Towbin J.A. .  ANKRD1, the Gene Encoding Cardiac Ankyrin Repeat Protein, Is a Novel Dilated Cardiomyopathy Gene .  Journal of the American College of Cardiology54 ( 4 ) 325 - 33   2009年7月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the American College of Cardiology  

    Objectives: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients. Background: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction. Methods: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction. Results: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP. Conclusions: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling. © 2009 American College of Cardiology Foundation.

    DOI: 10.1016/j.jacc.2009.02.076

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  • Arimura T., Inagaki N., Hayashi T., Shichi D., Sato A., Hinohara K., Vatta M., Towbin J.A., Chikamori T., Yamashina A., Kimura A. .  Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy .  Cardiovascular Research83 ( 1 ) 80 - 8   2009年7月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cardiovascular Research  

    Aims: Z-band alternatively spliced PDZ-motif protein (ZASP)/Cypher is a Z-disc component of which several dilated cardiomyopathy (DCM)-associated mutations have been reported. Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3 and both exons were expressed preferentially in the heart. The aim of this study was to investigate the functional alteration of ZASP/Cypher caused by the DCM-associated mutations. Methods and results: The yeast-two-hybrid method was used to identify the protein bound to a domain encoded by exon 4 of LDB3. Interaction of ZASP/Cypher with the binding protein was investigated in relation to the functional alterations caused by LDB3 mutations. Localization of the ZASP/Cypher-binding protein was examined at the cellular level in rat cardiomyocytes. Phosphoglucomutase 1 (PGM1), a metabolic enzyme involved in glycolysis and gluconeogenesis, was identified as a protein interacting with ZASP/Cypher. PGM1 bound to ZASP/Cypher at the domains encoded by exons 4 and 10. Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another mutation in exon 10 (Ile345Met) reduced the binding to PGM1. PGM1 showed diffuse localization in the cytoplasm of rat cardiomyocytes under standard culture conditions, and distribution at the Z-discs was observed under stressed culture conditions. Binding of endogenous PGM1 and ZASP/Cypher was found to be enhanced by stress in rat cardiomyocytes. Conclusion: ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The impaired binding of PGM1 to ZASP/Cypher might be involved in the pathogenesis of DCM. © The Author 2009.

    DOI: 10.1093/cvr/cvp119

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  • Arimura T., Hayashi Y., Murakami T., Oya Y., Funabe S., Arikawa-Hirasawa E., Hattori N., Nishino I., Kimura A. .  Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy .  Circulation Journal73 ( 1 ) 158 - 61   2009年1月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Journal  

    Background: Mutations in FKTN encoding for fukutin cause Fukuyama-type congenital muscular dystrophy characterized by severe muscle wasting and hypotonia with mental retardation. Fukuyama-type congenital muscular dystrophy is a recessive genetic trait. FKTN mutations in patients with dilated cardiomyopathy (DCM) have been investigated by our research group. The patients showed hyper-CKemia with mild or no muscle weakness and without mental retardation, suggesting that the clinical spectrum of FKTN mutations are wider than previously thought. The current study was designed to further explore the association of FKTN mutations with DCM or hypertrophic cardiomyopathy (HCM). Methods and Results: A total of 172 patients with DCM, 144 patients with familial HCM and 384 control individuals were analyzed for FKTN mutations. There was a DCM patient who was a compound heterozygote of a 3-kb insertion mutation and a missense mutation Cys101Phe. The patient showed hyper-CKemia with mild muscle involvement and no brain involvement. In contrast, 2 other DCM patients and 3 controls were heterozygous for the insertion mutation and normal allele, showing that the heterozygous insertion mutation itself was not associated with DCM. No mutation was found in the HCM patients. Conclusions: These observations indicated that the compound heterozygous FKTN mutation was a rare cause of DCM. Hyper-CKemia might be indicative of FKTN mutation in DCM.

    DOI: 10.1253/circj.CJ-08-0722

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  • Hinohara K., Nakajima T., Takahashi M., Hohda S., Sasaoka T., Nakahara K.I., Chida K., Sawabe M., Arimura T., Sato A., Lee B.S., Ban J.M., Yasunami M., Park J.E., Izumi T., Kimura A. .  Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations .  Journal of Human Genetics53 ( 4 ) 357 - 359   2008年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Human Genetics  

    Coronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR) = 1.30, 95% confidence interval (CI); 1.13-1.49, p = 0.00027, allele count model] and Koreans (OR = 1.19, 95% CI; 1.02-1.38, p = 0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians. © 2008 The Japan Society of Human Genetics and Springer.

    DOI: 10.1007/s10038-008-0248-4

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    その他リンク: http://search.jamas.or.jp/link/ui/2008277067

  • T Arimura, T Hayashi, A Kimura .  Molecular etiology of idiopathic cardiomyopathy. .  Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology26 ( 3 ) 153 - 8   2007年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Idiopathic cardiomyopathy (ICM) is a primary cardiac disorder associated with abnormalities of ventricular wall thickness, size of ventricular cavity, contraction, relaxation, conduction and rhythm. Over the past two decades, molecular genetic analyses have revealed that mutations in the various genes cause ICM and such information concerning the genetic basis of ICM enables us to speculate the pathogenesis of this heterogeous cardiac disease. This review focuses on the molecular pathogenesis, i.e., genetic abnormalities and functional alterations due to the mutations especially in sarcomere/cytoskeletal components, in three characteristic features of ICM, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). Understanding the functional abnormalities of the sarcomere/cytoskeletal components, in ICM, has unraveled the function of these components not only as a contractile unit but also as a pivot for transduction of biochemical signals.

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  • Noritsugu Nakano, Hisae Hori, Minako Abe, Hiroki Shibata, Takuro Arimura, Taishi Sasaoka, Motoji Sawabe, Kouji Chida, Tomio Arai, Ken-ichi Nakahara, Toru Kubo, Ken Sugimoto, Tomohiro Katsuya, Toshio Ogihara, Yoshinori Doi, Tohru Izumi, Akinori Kimura .  Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy. .  American journal of physiology. Heart and circulatory physiology293 ( 6 ) H3396-403   2007年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Elevated wall stress by hypertension induces an adaptive myocardial hypertrophy via releasing prohypertrophic hormones such as angiotensin II. In this study, we investigated the involvement of bone morphogenetic protein-10 (BMP10) in hypertension-induced cardiac hypertrophy. Expression of BMP10 was increased in the hypertrophied ventricles from hypertensive rats. BMP10 localized on cell surface and at stretch-sensing Z disc of cardiomyocytes, where BMP10 interacted with a protein called titin-cap (Tcap). A rare variant of the human BMP10 gene, Thr326Ile, was found to be associated with hypertensive dilated cardiomyopathy. The variant BMP10 demonstrated decreased binding to Tcap and increased extracellular secretion. Conditioned medium from cells transfected with wild-type or variant BMP10 induced hypertrophy in rat neonatal cardiomyocytes, except that medium from variant BMP10-carrying cells showed an enhanced effect reflecting the increased secretion. These observations suggested that hypertension induced expression of prohypertrophic BMP10, and the hypertrophic effect of BMP10 was modulated, at least in part, by its binding to Tcap at the Z disc.

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  • Takuro Arimura, Yuji Matsumoto, Osamu Okazaki, Takeharu Hayashi, Megumi Takahashi, Natsuko Inagaki, Kunihiko Hinohara, Naoto Ashizawa, Keisuke Yano, Akinori Kimura .  Structural analysis of obscurin gene in hypertrophic cardiomyopathy. .  Biochemical and biophysical research communications362 ( 2 ) 281 - 7   2007年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by left ventricular hypertrophy with diastolic dysfunction. Molecular genetic studies have revealed that HCM is caused by mutations in genes for sarcomere/Z-band components including titin/connectin and its associate proteins. However, disease-causing mutations can be found in about half of the patients, suggesting that other disease-causing genes remain to be identified. To explore a novel disease gene, we searched for obscurin gene (OBSCN) mutations in HCM patients, because obscurin interacts with titin/connectin. Two linked variants, Arg4344Gln and Ala4484Thr, were identified in a patient and functional analyses demonstrated that Arg4344Gln affected binding of obscurin to Z9-Z10 domains of titin/connectin, whereas Ala4484Thr did not. Myc-tagged obscurin showed that Arg4344Gln impaired obscurin localization to Z-band. These observations suggest that the obscurin abnormality may be involved in the pathogenesis of HCM.

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  • R Ben Yaou, A Toutain, T Arimura, L Demay, C Massart, C Peccate, A Muchir, S Llense, N Deburgrave, F Leturcq, K E Litim, N Rahmoun-Chiali, P Richard, D Babuty, D Récan-Budiartha, G Bonne .  Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism? .  Neurology68 ( 22 ) 1883 - 94   2007年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes. METHODS: Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin. RESULTS: Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C-->T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts. CONCLUSIONS: This highlights the crucial role of lamin A/C-emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery-Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.

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  • Takuro Arimura, Takeharu Hayashi, Yuji Matsumoto, Hiroki Shibata, Shitoshi Hiroi, Takeyuki Nakamura, Natsuko Inagaki, Kunihiko Hinohara, Megumi Takahashi, Satoh-Itoh Manatsu, Taishi Sasaoka, Toru Izumi, Gisèle Bonne, Ketty Schwartz, Akinori Kimura .  Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy. .  Biochemical and biophysical research communications357 ( 1 ) 162 - 7   2007年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilated ventricle and systolic dysfunction. Most of the DCM patients are sporadic cases, but a certain population of DCM patients can be familial cases caused by mutations in genes for sarcomere/Z-disc components including titin/connectin. However, disease-causing mutations could be identified only in a part of the familial DCM patients, suggesting that there should be other disease causing genes for DCM. To explore a novel disease gene for DCM, we searched for mutations in FHL2, encoding for four and half LIM protein 2 (FHL2) in DCM patients, because FHL2 is known to associate with titin/connectin. A missense mutation, Gly48Ser, was identified in a patient with familial DCM. Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. Because FHL2 protein is known to tether metabolic enzymes to titin/connectin, these observations suggest that the Gly48Ser mutation may be involved in the pathogenesis of DCM via impaired recruitment of metabolic enzymes to the sarcomere.

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  • Antoine Muchir, Paul Pavlidis, Valérie Decostre, Alan J Herron, Takuro Arimura, Gisèle Bonne, Howard J Worman .  Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. .  The Journal of clinical investigation117 ( 5 ) 1282 - 93   2007年5月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mutations in LMNA, which encodes nuclear Lamins A and C cause diseases affecting various organs, including the heart. We have determined the effects of an Lmna H222P mutation on signaling pathways involved in the development of cardiomyopathy in a knockin mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy. Analysis of genome-wide expression profiles in hearts using Affymetrix GeneChips showed statistically significant differences in expression of genes in the MAPK pathways at the incipience of the development of clinical disease. Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. In heart tissue and isolated cardiomyocytes, there was activation of MAPK cascades and downstream targets, implicated previously in the pathogenesis of cardiomyopathy. Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes. Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy.

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  • Natsuko Inagaki, Takeharu Hayashi, Takuro Arimura, Yoshinori Koga, Megumi Takahashi, Hiroki Shibata, Kunihiko Teraoka, Taishiro Chikamori, Akira Yamashina, Akinori Kimura .  Alpha B-crystallin mutation in dilated cardiomyopathy. .  Biochemical and biophysical research communications342 ( 2 ) 379 - 86   2006年4月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mutations in genes for sarcomeric proteins such as titin/connectin are known to cause dilated cardiomyopathy (DCM). However, disease-causing mutations can be identified only in a small proportion of the patients even in the familial cases, suggesting that there remains yet unidentified disease-causing gene(s) for DCM. To explore the novel disease gene for DCM, we examined CRYAB encoding alphaB-crystallin for mutation in the patients with DCM, since alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin, and we previously reported a N2B mutation, Gln4053ter, in DCM. A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient and the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins. Functional analysis revealed that the mutation decreased the binding to titin/connectin heart-specific N2B domain without affecting distribution of the mutant crystallin protein in cardiomyocytes. In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein. These observations suggest that the Arg157His mutation may be involved in the pathogenesis of DCM via impaired accommodation to the heart-specific N2B domain of titin/connectin and its disease-causing mechanism is different from the mutation found in desmin-related myopathy.

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  • Takuro Arimura, Anne Helbling-Leclerc, Catherine Massart, Shaida Varnous, Florence Niel, Emmanuelle Lacène, Yves Fromes, Marcel Toussaint, Anne-Marie Mura, Dagmar I Keller, Helge Amthor, Richard Isnard, Marie Malissen, Ketty Schwartz, Gisèle Bonne .  Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. .  Human molecular genetics14 ( 1 ) 155 - 69   2005年1月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.

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  • Rabah Ben Yaou, Antoine Muchir, Takuro Arimura, Catherine Massart, Laurence Demay, Pascale Richard, Gisèle Bonne .  Genetics of laminopathies. .  Novartis Foundation symposium264   81 - 90   2005年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy.

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  • Yuji Matsumoto, Takeharu Hayashi, Natsuko Inagaki, Megumi Takahashi, Shitoshi Hiroi, Takeyuki Nakamura, Takuro Arimura, Kazufumi Nakamura, Naoto Ashizawa, Michio Yasunami, Toru Ohe, Katsusuke Yano, Akinori Kimura .  Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy. .  Journal of muscle research and cell motility26 ( 6-8 ) 367 - 74   2005年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of "idiopathic" cardiomyopathy. Recent molecular genetic analyses have now revealed that "idiopathic" cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy-associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.

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  • Takeharu Hayashi, Takuro Arimura, Manatsu Itoh-Satoh, Kazuo Ueda, Shigeru Hohda, Natsuko Inagaki, Megumi Takahashi, Hisae Hori, Michio Yasunami, Hirofumi Nishi, Yoshinori Koga, Hiroshi Nakamura, Masunori Matsuzaki, Bo Yoon Choi, Sung Won Bae, Cheol Woon You, Kyung Hoon Han, Jeong Euy Park, Ralph Knöll, Masahiko Hoshijima, Kenneth R Chien, Akinori Kimura .  Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. .  Journal of the American College of Cardiology44 ( 11 ) 2192 - 201   2004年12月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: We sought to explore the relationship between a Tcap gene (TCAP) abnormality and cardiomyopathy. BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc. METHODS: The TCAP was analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays-yeast two-hybrid and glutathion S-transferase pull-down competition-were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q. RESULTS: Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1. CONCLUSIONS: These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.

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  • A Muchir, J Medioni, M Laluc, C Massart, T Arimura, A J van der Kooi, I Desguerre, M Mayer, X Ferrer, S Briault, M Hirano, H J Worman, A Mallet, M Wehnert, K Schwartz, G Bonne .  Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. .  Muscle & nerve30 ( 4 ) 444 - 50   2004年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.

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  • Kazuo Ueda, Kazufumi Nakamura, Takeharu Hayashi, Natsuko Inagaki, Megumi Takahashi, Takuro Arimura, Hiroshi Morita, Yasushi Higashiuesato, Yuji Hirano, Michio Yasunami, Shuichi Takishita, Akira Yamashina, Tohru Ohe, Makoto Sunamori, Masayasu Hiraoka, Akinori Kimura .  Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. .  The Journal of biological chemistry279 ( 26 ) 27194 - 8   2004年6月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.

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  • Kyoung-Youl Lee, Makoto Shibutani, Hironori Takagi, Takuro Arimura, Shu Takigami, Chikako Uneyama, Natsumi Kato, Masao Hirose .  Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats. .  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association42 ( 4 ) 687 - 95   2004年4月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A subchronic toxicity study of N-acetylglucosamine (GlcNAc), a monomeric form of chitin, was conducted in groups of 10 male and 10 female F344 rats fed pelleted diets containing 0, 0.625, 1.25, 2.5 or 5% concentrations for 13 weeks. All animals survived until the end of the experiment. Slight, non-significant increase in body weights was observed in males receiving 0.625, 1.25 or 2.5% from week 4 until the end of the experiment, when significant elevation was found for the males receiving 0.625, 1.25 or 2.5% at the terminal sacrifice to result in decreased relative weights of many organs in these cases. However, there were no obvious indications of toxicity in any group receiving GlcNAc in terms of clinical signs, food intake, hematology, serum biochemistry, and histopathological findings. Thus, it was concluded that orally administered GlcNAc exerts no obvious toxicity to F344 rats at concentrations up to 5% in the diet for 13 weeks. Based on the present toxicity data, > or =5% was determined to be a no-observed-adverse-effect level, translated into 2476 and 2834 mg/kg/day for male and female rats, respectively.

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  • Takuro Arimura, Takeharu Hayashi, Hajime Terada, Su-Yeoun Lee, Qiang Zhou, Megumi Takahashi, Kazuo Ueda, Tatsuhito Nouchi, Shigeru Hohda, Makoto Shibutani, Masao Hirose, Ju Chen, Jeong-Euy Park, Michio Yasunami, Hideharu Hayashi, Akinori Kimura .  A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C. .  The Journal of biological chemistry279 ( 8 ) 6746 - 52   2004年2月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dilated cardiomyopathy is characterized by ventricular dilation with systolic dysfunction of cardiac muscle. Recent genetic studies have revealed that mutations in genes for cytoskeleton proteins distributed in the Z-disc and/or intercalated discs of the cardiac muscle are major predictors of cardiomyopathy. However, as mutations in these genes can account for only a part of the patient population, there should be another disease-causing gene(s) for cardiomyopathy. Cypher/ZASP appears to be an ideal candidate for the cardiomyopathy causative gene, because Cypher/ZASP encodes a Z-disc associated protein, and recent studies have demonstrated that Cypher/ZASP knock-out mice develop cardiomyopathy. In this study, we searched for sequence variations in Cypher/ZASP in 96 unrelated Japanese patients with dilated cardiomyopathy. A D626N mutation located within the third LIM domain was identified in a familial case but not found in the unrelated controls. A family study of the patient showed that all affected siblings tested had the same mutation. Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy. To reveal the biochemical changes due to the mutation, we performed a yeast two-hybrid assay and a pull-down assay. It was demonstrated by both assays that the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C, suggesting a novel biochemical mechanism of the pathogenesis of dilated cardiomyopathy.

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  • Takeharu Hayashi, Takuro Arimura, Kazuo Ueda, Hiroki Shibata, Shigeru Hohda, Megumi Takahashi, Hisae Hori, Yoshinori Koga, Naoki Oka, Tsutomu Imaizumi, Michio Yasunami, Akinori Kimura .  Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. .  Biochemical and biophysical research communications313 ( 1 ) 178 - 84   2004年1月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are caused by mutations in 14 and 15 different disease genes, respectively, in a part of the patients and the disease genes for cardiomyopathy overlap in part with that for limb-girdle muscular dystrophy (LGMD). In this study, we examined an LGMD gene encoding caveolin-3 (CAV3) for mutation in the patients with HCM or DCM. A Thr63Ser mutation was identified in a sibling case of HCM. Because the mutation was found at the residue that is involved in the LGMD-causing mutations, we investigate the functional change due to the Thr63Ser mutation as compared with the LGMD mutations by examining the distribution of GFP-tagged CAV3 proteins. It was observed that the Thr63Ser mutation reduced the cell surface expression of caveolin-3, albeit the change was mild as compared with the LGMD mutations. These observations suggest that HCM is a clinical spectrum of CAV3 mutations.

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  • Manatsu Itoh-Satoh, Takeharu Hayashi, Hirofumi Nishi, Yoshinori Koga, Takuro Arimura, Takeshi Koyanagi, Megumi Takahashi, Shigeru Hohda, Kazuo Ueda, Tatsuhito Nouchi, Michiaki Hiroe, Fumiaki Marumo, Tsutomu Imaizumi, Michio Yasunami, Akinori Kimura .  Titin mutations as the molecular basis for dilated cardiomyopathy. .  Biochemical and biophysical research communications291 ( 2 ) 385 - 93   2002年2月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dilated cardiomyopathy (DCM) is a heterogeneous cardiac disease characterized by ventricular dilatation and systolic dysfunction. Recent genetic studies have revealed that mutations in genes for cardiac sarcomere components lead to DCM. The cardiac sarcomere consists of thick and thin filaments and a giant protein, titin. Because one of the loci of familial DCM was mapped to the region of the titin gene, we searched for titin mutations in the patients and identified four possible disease-associated mutations. Two mutations, Val54Met and Ala743Val, were found in the Z-line region of titin and decreased binding affinities of titin to Z-line proteins T-cap/telethonin and alpha-actinin, respectively, in yeast two-hybrid assays. The other two mutations were found in the cardiac-specific N2-B region of titin and one of them was a nonsense mutation, Glu4053ter, presumably encoding for a truncated nonfunctional molecule. These observations suggest that titin mutations may cause DCM in a subset of the patients.

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  • N Obuchi, M Takahashi, T Nouchi, M Satoh, T Arimura, K Ueda, J Akai, M Ota, T Naruse, H Inoko, F Numano, A Kimura .  Identification of MICA alleles with a long Leu-repeat in the transmembrane region and no cytoplasmic tail due to a frameshift-deletion in exon 4. .  Tissue antigens57 ( 6 ) 520 - 35   2001年6月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MHC class I chain-related gene A (MICA) is located close to HLA-B gene and expressed in epithelial cells. The MICA gene is reported to be highly polymorphic as are the classical class I genes. To further assess the polymorphism in the MICA gene, we analyzed a total of 60 HLA-homozygous cells for the sequences spanning exons 2-6. In the analysis, four new MICA alleles were identified and six variations were recognized in exon 6. MICA*017, which was identified in three HLA-B57 homozygous cells (DBB, DEM and WIN), differed from MICA*002 in exon 3 and had a guanine deletion at the 3' end of exon 4. MICA*015 identified in an HLA-B45 homozygous cell (OMW) also had the same deletion that causes a frameshift mutation resulting in complete change of the transmembrane region and premature termination in the cytoplasmic tail; these alleles have a long hydrophobic leucine-rich region instead of the alanine repeat in the transmembrane region and terminate at the second position in the cytoplasmic domain. The frameshift deletion was found only in HLA-B45- or -B57-positive panels tested, suggesting a strong linkage disequilibrium between the deletion and B45 or B57. MICA*048, which was different in exon 5 from MICA*008, was identified in an HLA-B61 homozygous cell (TA21), while MICA*00901 identified in HLA-B51 homozygous cells (LUY and KT2) was distinguished from MICA*009 by exon 6.

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  • T Arimura, N Suematsu, Y B Zhou, J Nishimura, S Satoh, A Takeshita, H Kanaide, A Kimura .  Identification, characterization, and functional analysis of heart-specific myosin light chain phosphatase small subunit. .  The Journal of biological chemistry276 ( 9 ) 6073 - 82   2001年3月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myosin light chain phosphatase consists of three subunits, a 38-kDa catalytic subunit, a large 110-130-kDa myosin binding subunit, and a small subunit of 20-21 kDa. The catalytic subunit and the large subunit have been well characterized. The small subunit has been cloned and studied from smooth muscle, but little is known about its function and specificity in the other muscles such as cardiac muscle. In this study, cDNAs for heart-specific small subunit isoforms, hHS-M(21), were isolated and characterized. Evidence was obtained from an analysis of genome to suggest that the small subunit was the product of the same gene as the large subunit. Using permeabilized renal artery preparation and permeabilized cardiac myocytes, it was shown that the small subunit increased sensitivity to Ca(2+) in muscle contraction. It was also shown using an overlay assay that hHS-M(21) bound the large subunit. Mapping experiments demonstrated that the binding domain and the domain involved in the increasing Ca(2+) sensitivity mapped to the same N-terminal region of hHS-M(21). These observations suggest that the heart-specific small subunit hHS-M(21) plays a regulatory role in cardiac muscle contraction by its binding to the large subunit.

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  • A Kimura, M Ito-Satoh, T Hayashi, M Takahashi, T Arimura .  Molecular etiology of idiopathic cardiomyopathy in Asian populations. .  Journal of cardiology37 Suppl 1 ( Suppl.I ) 139 - 46   2001年査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本心臓病学会  

    BACKGROUND: Idiopathic cardiomyopathy was by definition a disease of unknown etiology and there are two major clinical forms, hypertrophic cardiomyopathy and dilated cardiomyopathy. Recent molecular genetic analyses have now revealed that mutations in genes for sarcomere cause hypertrophic cardiomyopathy leading to a hypothesis of hypertrophic cardiomyopathy as sarcomeropathy. On the other hand, mutations in genes for Z-disc component cause dilated cardiomyopathy speculating that dilated cardiomyopathy is cytoskeletopathy at least in part. METHODS: A large panel of Asian patients and families with hypertrophic cardiomyopathy or dilated cardiomyopathy was analyzed for gene abnormalities in all exons and adjacent introns of the known disease-related genes and in a part of several candidates of novel disease-related genes. RESULTS: Mutations in the genes for sarcomere were found in 47% of familial cases and 14% of sporadic cases of hypertrophic cardiomyopathy and there were locus and allelic differences in clinical phenotypes of hypertrophic cardiomyopathy patients. In contrast, only a few patients with dilated cardiomyopathy were identified for mutations in the known disease-causing genes. Mutations in the gene for titin, a giant molecule linking Z-disc with sarcomere components, were found in hypertrophic cardiomyopathy patients. CONCLUSIONS: The molecular etiologies of cardiomyopathy can be identified in about half of hypertrophic cardiomyopathy and a small part of dilated cardiomyopathy, suggesting that there are several novel disease-causing genes. Identification of titin mutation in hypertrophic cardiomyopathy indicate that hypertrophic cardiomyopathy is in part considered as the cytoskeletopathy.

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  • T Arimura, T Nakamura, S Hiroi, M Satoh, M Takahashi, N Ohbuchi, K Ueda, T Nouchi, N Yamaguchi, J Akai, A Matsumori, S Sasayama, A Kimura .  Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy. .  Human genetics107 ( 5 ) 440 - 51   2000年11月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled heart with systolic dysfunction of unknown etiology. Because abnormalities in genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence variations were searched for in Japanese patients with IDC and healthy controls. The nebulette gene consists of 28 exons, and four sequence variations leading to amino acid replacement (Gln187His, Met351Val, Asn654Lys, and Thr728Ala) were identified in the patients. These variations were also found in the healthy controls and hence they were polymorphisms and not disease-specific mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozygotes for Lys at codon 654, a variant at a relatively conserved residue in an actinbinding motif, was significantly increased in nonfamilial IDC patients (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1.21%, OR=6.25, P=0.002, 95% CI=1.92-20.29), while this association was not found in familial IDC patients (n=24). These observations suggest that the nebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.

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  • A Kimura, Y Kobayashi, M Takahashi, N Ohbuchi, H Kitamura, T Nakamura, M Satoh, T Sasaoka, S Hiroi, T Arimura, J Akai, W Aerbajinai, Y Yasukochi, F Numano .  MICA gene polymorphism in Takayasu's arteritis and Buerger's disease. .  International journal of cardiology66 Suppl 1   S107-13; discussion S115   1998年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To further clarify the HLA-linked genes susceptible to arterio-vasculitis of unknown etiology, Takayasu's arteritis and Buerger's disease, polymorphism in the MICA gene, a newly identified gene near the HLA-B gene and expressed in epithelial cell lineage, was investigated. Polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis and subsequent sequencing of the MICA gene have revealed that there are 5 MICA alleles which are different in the number of a GCT repeat in exon 5: MICA alleles MICA-1.1, -1.2, -1.3 and -1.4 have 9, 6, 5 and 4 GCT repeats, respectively, and MICA-1.5 has 5 GCT repeats with a 1 bp frameshift insertion in the repeat. MICA genotyping data in 81 Japanese patients with Takayasu's arteritis, 38 Japanese patients with Buerger's disease, and 160 healthy Japanese controls showed that MICA-1.2 and -1.4 were significantly associated with Takayasu's arteritis and Buerger's disease, respectively. Because MICA-1.2 and -1.4 were in strong linkage disequilibria with HLA-B52 and -B54 in the Japanese populations, respectively, we have compared the odds ratio (OR) of the risk to the diseases for individuals having both or each of the disease-associated MICA and HLA-B alleles. It was found that MICA-1.2 gave a significantly high OR of risk to Takayasu's arteritis in the absence of HLA-B52, suggesting that the HLA-linked gene susceptible to Takayasu's arteritis is mapped near the MICA gene. In contrast, MICA-1.4 gave a significantly high OR of risk to Buerger's disease only in the presence of HLA-B54, suggesting that the HLA-linked gene susceptible to Buerger's disease is linked to the HLA-B54-MICA-1.4 haplotype, and may be differently mapped from that to Takayasu's arteritis.

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  • N Machida, T Arimura, Y Otagiri, K Kiryu, T Oka .  Epithelioid haemangioendothelioma of the lung in a dog. .  Journal of comparative pathology119 ( 3 ) 317 - 22   1998年10月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epithelioid haemangioendothelioma of the lung was found in a 9-year-old female dog. The tumour occurred bilaterally in the form of multiple, discrete, small nodular lesions with a similar histological appearance. The lesions were characterized by a hypocellular sclerotic core surrounded by a more cellular peripheral zone, from which the tumour tissue extended into the adjacent alveolar spaces and bronchioles in a micropolypoid manner, filling their lumina. In addition, invasion of the pulmonary vessels was frequently observed within, around, and at a distance from the nodular neoplastic lesions. Most of the tumour cells had abundant eosinophilic cytoplasm, large, round or oval nuclei, and occasional intracytoplasmic vacuoles containing red blood cells. By means of immunolabelling, factor VIII-related antigen, a marker for endothelial cells, was detected within the cytoplasm of a small proportion (< 5%) of the tumour cells. This appears to be the first report of such a tumour in an animal other than man.

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  • T Arimura, N Machida, Y Nishida, K Kiryu .  Fatal rupture of the brachiocephalic artery in a dog. .  Journal of comparative pathology118 ( 2 ) 151 - 4   1998年2月査読 国際誌

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A case of arterial rupture that caused sudden death in a 3-year-old dog is presented. Rupture of the brachiocephalic artery was located just distal to the origin of the left common carotid artery. Histological examination of the vessel wall revealed necrosis of the media.

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▼全件表示

書籍等出版物

  • Molecular etiology of idiopathic cardiomyopathy: Identification of novel disease genes for hypertrophic cardiomyopathy and dilated cardiomyopathy.

    Kimura A, Hayashi T, Itoh-Satoh M, Arimura T, Lee WH, Lee SY, Park JE( 担当: 共著)

    Cardiomyopathies and Heart Failure; Biomolecular, Infectious and Immune Mechanisms, Klumer Academic Publishers.  2003年 

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    記述言語:英語 著書種別:学術書

  • Mutational profiles and molecular pathogenesis of hypertrophic cardiomyopathy and dilated cardiomyopathy in Asian populations.

    Kimura A, Itoh-Satoh M, Hayashi T, Takahashi M, Arimura T, Yasunami M, Lee SY, Hwang TH, Lee WH, Park JE( 担当: 共著)

    Frontiers in Cardiovascular Health, Klumer Academic Publishers.  2003年 

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    記述言語:英語 著書種別:学術書

MISC

  • 教育の質の向上は自己評価から始まる-なぜ国際認証を受けるのか- 国際的な教育認証で求められる品質保証の在り方と取り組み

    有村 卓朗

    日本獣医学会学術集会講演要旨集   164回   [V4 - 3]   2021年9月

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    記述言語:日本語   出版者・発行元:(公社)日本獣医学会  

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  • 医療専門職養成の質保証 獣医学教育の国際認証について

    有村 卓朗

    医学教育   51 ( Suppl. )   28 - 28   2020年7月

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    記述言語:日本語   出版者・発行元:(一社)日本医学教育学会  

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  • 国際認証取得への道のり EAEVE認証取得へ向けたVetJapan Southの取り組み

    有村 卓朗

    日本獣医学会学術集会講演要旨集   162回   155 - 155   2019年8月

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    記述言語:日本語   出版者・発行元:(公社)日本獣医学会  

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  • 4大学連携による獣医学教育の改善 VetJapan SouthにおけるEAEVE認証取得への取り組み

    宮本 篤, 有村 卓朗, 三角 一浩, 三好 宣彰, 奥田 優, 度会 雅久, 佐藤 晃一

    日本獣医学会学術集会講演要旨集   161回   156 - 156   2018年8月

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    記述言語:日本語   出版者・発行元:(公社)日本獣医学会  

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  • 家族性拡張型心筋症に対する抗アンドロゲン療法の効果

    中野 知哉, 尾上 健児, 坂口 泰弘, 有村 卓朗, 木村 彰方, 斎藤 能彦

    日本内分泌学会雑誌   92 ( 3 )   901 - 901   2017年1月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

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  • 全エクソームシーケンシングにより明らかになった家族性洞不全症候群に対するサルコメア遺伝子MYPNの新規スプライシング変異の関与(A Novel Splicing Mutation in a Sarcomeric Gene MYPN Responsible for Familial Sick Sinus Syndrome Identified by Whole Exome Sequencing)

    Ishikawa Taisuke, Kowase Shinya, Kurosaki Kenji, Nogami Akihiko, Kimura Akinori, Arimura Takuro, Makita Naomasa, Tsuji Yukiomi, Harrell Daniel

    Circulation Journal   79 ( Suppl.I )   1107 - 1107   2015年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Up Regulation of Autophagy in Hsp60 Mutant Heart is an Adaptive Response to Increased Oxidative Stress and Causes Cardiomyopathy

    Hirokazu Enomoto, Shinji Makino, Nishant Mittel, Akinori Kimura, Takuro Arimura, Takeharu Hayashi, Takayuki Inomata, Keiichi Fukuda

    CIRCULATION   130   2014年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Web of Science

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  • A novel cardiac alpha-myosin heavy chain (MYH6) mutation impairing sarcomere structure responsible for familial sick sinus syndrome

    T. Ishikawa, A. Nogami, S. Kowase, D. Harrell, Y. Tsuji, T. Arimura, A. Kimura, N. Makita

    EUROPEAN HEART JOURNAL   35   1034 - 1034   2014年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS  

    Web of Science

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  • 心房のミオシン重鎖コーディング遺伝子MYH6の新規変異は洞不全症候群を引き起こす(A Novel Mutation in Atrial Myosin Heavy Chain Coding Gene MYH6 Causes Sick Sinus Syndrome)

    Ishikawa Taisuke, Nogami Akihiko, Kowase Shinya, Harrell Daniel T., Arimura Takuro, Tsuji Yukiomi, Kimura Akinori, Makita Naomasa

    心電図   34 ( Suppl.3 )   418 - 418   2014年6月

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    記述言語:英語   出版者・発行元:(一社)日本不整脈心電学会  

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  • 家族性洞不全症候群患者に同定された心房型ミオシン重鎖遺伝子(MYH6)変異と機能解析

    石川 泰輔, 小和瀬 晋弥, 有村 卓朗, 野上 昭彦, 辻 幸臣, 木村 彰方, 蒔田 直昌

    日本生理学雑誌   76 ( 3 )   83 - 84   2014年5月

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    記述言語:日本語   出版者・発行元:(一社)日本生理学会  

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  • 肥大型心筋症iPS細胞由来の心筋細胞においてEndothelin-1は収縮変動を誘発する(Endothelin-1 Induces Contraction Variability in Hypertrophic Cardiomyopathy-iPS Cell-derived Cardiomyocytes)

    Tanaka Atsushi, Yuasa Shinsuke, Egashira Toru, Seki Tomohisa, Kodaira Masaki, Kusumoto Dai, Yae Kojiro, Kuroda Yusuke, Okata Shinichiro, Suzuki Tomoyuki, Arimura Takuro, Kimura Kensuke, Furukawa Tetsushi, Kimura Akinori, Node Koichi, Fukuda Keiichi

    Circulation Journal   78 ( Suppl.I )   7 - 8   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Heat Shock Protein 60(hsp60)の変異は心筋症感受性を高める(Mutation of Heat Shock Protein 60 (hsp60) Increases Susceptibility to Cardiomyopathy)

    Enomoto Hirokazu, Makino Shinji, Mittal Nishant, Yamamoto Tatsumi, Arimura Takurou, Kimura Akinori, Inomata Takayuki, Fukuda Keiichi

    Circulation Journal   78 ( Suppl.I )   356 - 357   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心房型ミオシン重鎖コーディング遺伝子MYH6の新規変異は洞不全症候群を引き起こす(A Novel Mutation in Atrial Myosin Heavy Chain Coding Gene MYH6 Causes Sick Sinus Syndrome)

    Ishikawa Taisuke, Nogami Akihiko, Kowase Shinya, Arimura Takuro, Kimura Akinori, Makita Naomasa

    Circulation Journal   78 ( Suppl.I )   116 - 116   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心筋肥大および心不全の分子機序 Lamin A/C変異起因によるる心不全における性差の分子機序(Molecular Mechanism for Myocardial Hypertrophy and Heart Failure Molecular Mechanism of Gender Difference in Heart Failure Caused by Lamin A/C Mutations)

    Kimura Akinori, Arimura Takuro, Onoue Kenji, Ishikawa Taisuke, Saito Yoshihiko

    Circulation Journal   78 ( Suppl.I )   133 - 133   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心筋肥大および心不全の分子機序 魚モデルおよび患者においてTitin/MURF1シグナル複合体の撹乱は心筋肥大と関連する(Molecular Mechanism for Myocardial Hypertrophy and Heart Failure Perturbation of the Titin/MURF1 Signaling Complex is Associated with Cardiac Hypertrophy in a Fish Model and in Human Patients)

    Makino Shinji, Higashikuse Yuta, Arimura Takurou, Kawakami Atsushi, Kudo Akira, Oda Mayumi, Labeit Siegfried, Furukawa Tetsushi, Kimura Akinori, Fukuda Keiichi

    Circulation Journal   78 ( Suppl.I )   132 - 132   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • トロポニンI遺伝子(TNNI3)の点変異(Ala161Asp)を認めた家族性肥大型心筋症の一例

    河合 秀樹, 森本 紳一郎, 高桑 蓉子, 服部 晃左, 加藤 靖周, 皿井 正義, 渡邉 英一, 有村 卓朗, 木村 彰方, 尾崎 行男

    日本心臓病学会誌   8 ( Suppl.I )   415 - 415   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • β-Cardiac Myosin Heavy Chain(MYH7)遺伝子の新規点変異をみとめた肥大型心筋症の12歳男児例

    岡田 清吾, 鈴木 康夫, 有村 卓朗, 木村 彰方, 鳴海 宏子, 長谷川 俊史

    日本小児循環器学会雑誌   29 ( Suppl. )   s353 - s353   2013年6月

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    記述言語:日本語   出版者・発行元:(NPO)日本小児循環器学会  

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  • ブルガダ症候群に関連する新規SCN3B変異はNav1.5の細胞内輸送と機能に影響を与える(A Novel SCN3B Mutation Associated with Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5)

    Ishikawa Taisuke, Takahashi Naohiko, Ohno Seiko, Sakurada Harumizu, Nakamura Kazufumi, Makiyama Takeru, Horie Minoru, Arimura Takuro, Makita Naomasa, Kimura Akinori

    Circulation Journal   77 ( Suppl.I )   216 - 216   2013年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Lmna変異ノックインマウスモデルにおいてtestosteroneが拡張型心筋症の進行に及ぼす影響(Impact of Testosterone on Progression of Dilated Cardiomyopathy in a Lmna-mutation Knock-in Mouse Model)

    Arimura Takuro, Ishikawa Taisuke, Kimura Akinori

    Circulation Journal   77 ( Suppl.I )   65 - 65   2013年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 家族性WPW症候群の1家系における臨床像の検討

    稲川 浩平, 相澤 義泰, 高月 誠司, 勝俣 良紀, 西山 崇比古, 木村 雄弘, 西山 信大, 福本 耕太郎, 谷本 陽子, 谷本 耕司郎, 湯浅 慎介, 西森 健雄, 稲垣 雅行, 有村 卓朗, 木村 彰方, 三田村 秀雄, 福田 恵一

    心電図   32 ( Suppl.5 )   S - 155   2012年9月

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    記述言語:日本語   出版者・発行元:(一社)日本不整脈心電学会  

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  • NFKBIL1はヒトおよびウイルス遺伝子のスプライシングを制御する

    安 健博, 中島 敏晶, 柴田 宏樹, 成瀬 妙子, 有村 卓朗, 安波 道郎, 木村 彰方

    MHC: Major Histocompatibility Complex   19 ( 2 )   149 - 149   2012年8月

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    記述言語:日本語   出版者・発行元:日本組織適合性学会  

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  • 拡張型心筋症関連BAG3変異はZ-discの構築を障害し、心筋細胞のアポトーシス感受性を増強する(Dilated Cardiomyopathy-associated BAG3 Mutations Impair the Z-disc Assembly and Enhance the Sensitivity to Apoptosis in Cardiomyocytes)

    Arimura Takuro, Ishikawa Taisuke, Nunoda Shinichi, Kawai Sachio, Kimura Akinori

    Circulation Journal   76 ( Suppl.I )   884 - 884   2012年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Brugada症候群の新規機序 Sarcolemmal membrane-associated protein(SLMAP)遺伝子変異によるhNav1.5機能の障害(A Novel Mechanism of Brugada Syndrome: Mutation of Sarcolemmal Membrane-associated Protein (SLMAP) Gene Impaired hNav1.5 Function)

    Ishikawa Taisuke, Sato Akinori, Arimura Takuro, Sakurada Harumizu, Makita Naomasa, Kimura Akinori

    Circulation Journal   76 ( Suppl.I )   779 - 779   2012年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心室細動を契機に発見された心尖部瘤を伴う心室中部閉塞性肥大型心筋症の1例

    古賀 俊輔, 小林 欣夫, 長谷川 洋, 康田 典鷹, 李 光浩, 上田 希彦, 船橋 伸禎, 有村 卓, 木村 彰方, 永井 敏雄

    心臓   44 ( 11 )   1399 - 1404   2012年

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    記述言語:日本語   出版者・発行元:公益財団法人 日本心臓財団  

    症例は43歳,男性.幼少時より心電図異常を指摘されていた.某年6月某日,自宅安静時に突然意識を消失し,家族により心肺蘇生が施行され,救急隊により自動体外式除細動器(automated external defibrillator;AED)で除細動され洞調律に復帰し,前医へ搬送された.第9病日に心室細動(ventricular fibrillation;VF)に対する植込み型除細動器(implantable cardioverter defibrillator;ICD)植え込み目的で当院転院となり,心エコー,心臓CTにて,瘤内血栓を伴う左室心尖部瘤と心室中部閉塞性肥大型心筋症を認め,第12病日にICD植え込み術を施行した.心室内血栓はヘパリンとワルファリンにて消失し,経過良好にて退院となった.心尖部瘤を合併した肥大型心筋症では,文献的にも心室頻拍やVFといった致死的不整脈の出現する危険性が高く,心室中部閉塞性肥大型心筋症に心尖部瘤を伴う症例では突然死や致死性不整脈のリスクが有意に上昇することが知られている.したがって,本症例においてもハイリスクとして管理する必要があり,心尖部瘤を合併した心室中部閉塞性肥大型心筋症では突然死の予防としてICDを積極的に考慮する必要があると考えられた.

    DOI: 10.11281/shinzo.44.1399

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  • 心臓特異的なmyosin light chain phosphatase低分子サブユニットはRho-assoicated kinaseを活性化させてmyosin phosphatase target subunit 1のリン酸化を調節する(Heart-specific Small Subunit of Myosin Light Chain Phosphatase Activates Rho-associated Kinase and Regulates Phosphorylation of Myosin Phosphatase Target Subunit 1)

    Arimura Takuro, Ishikawa Taikuse, Kimura Akinori

    Circulation Journal   75 ( Suppl.I )   122 - 123   2011年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • メダカおよびヒトではtitinのMバンド領域におけるミスセンス変異が拡張型心筋症の原因となる(Missense Mutation in the M-band Region of titin Leads to Hypertrophic Cardiomyopathy in Medaka Fish and Human)

    Higashikuse Yuta, Makino Shinji, Yoon Sung Han, Oda Mayumi, Kageyama Toshimi, Yuasa Shinsuke, Kaneda Ruri, Murata Mitsushige, Sano Motoaki, Kudo Akira, Kawakami Atsushi, Kimura Akinori, Arimura Takuro, Morizane Shintaro, Suzuki Takeshi, Fukuda Keiichi

    Circulation Journal   75 ( Suppl.I )   127 - 127   2011年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心筋ミオシン軽鎖リン酸化制御に基づく心不全新規治療戦略

    有村 卓朗

    心臓   41 ( 12 )   1407 - 1407   2009年12月

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    記述言語:日本語   出版者・発行元:(公財)日本心臓財団  

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  • Characterization of Emd-/-LmnaH222P/H222P double mutant mice

    W. C. Liang, Y. K. Hayashi, Y. E. Park, H. Mitsuhashi, T. Arimura, G. Bonne, S. Noguchi, I. Nishino

    NEUROMUSCULAR DISORDERS   19 ( 8-9 )   648 - 648   2009年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2009.06.324

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  • Autophagic degradation of nuclear component in nuclear envelopathy

    Y. E. Park, Y. K. Hayashi, G. Bonne, T. Arimura, S. Noguchi, I. Nonaka, I. Nishino

    NEUROMUSCULAR DISORDERS   19 ( 8-9 )   647 - 647   2009年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.nmd.2009.06.321

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  • FRS-090 Identification of a Novel Disease Gene for Hypertrophic Cardiomyopathy(FRS19,Genetic Abnormalities in Cardiac Hypertrophy and Cardiomyopathy (M),Featured Research Session (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)

    Arimura Takuro, Bos J. Martijn, Satoh Akinori, Kubo Toru, Okamoto Hiroshi, Nishi Hirofumi, Harada Haruhito, Koga Yoshinori, Doi Yoshinori, Ackerman Michael J., Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   73 ( 0 )   161 - 161   2009年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

    CiNii Books

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  • 心臓肥大と心筋症における遺伝子異常 肥大型心筋症の新規疾患遺伝子の同定(Genetic Abnormalities in Cardiac Hypertrophy and Cardiomyopathy Identification of a Novel Disease Gene for Hypertrophic Cardiomyopathy)

    Arimura Takuro, Bos J. Martijn, Satoh Akinori, Kubo Toru, Okamoto Hiroshi, Nishi Hirofumi, Harada Haruhito, Koga Yoshinori, Doi Yoshinori, Ackerman Michael J., Kimura Akinori

    Circulation Journal   73 ( Suppl.I )   161 - 161   2009年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 特発性心筋症モデルマウスの作製とその病態解析 ヒトからマウスへ、マウスからヒトへ

    有村 卓朗, 木村 彰方

    循環器科   65 ( 2 )   212 - 212   2009年2月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • PJ-201 A Compound Heterozygous Mutation in KCNQ1 Associated with Long QT Syndrome(Arrhythmia, basic(05)(A),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

    Sato Akinori, Arimura Takuro, Aizawa Yoshiyasu, Ushinohama Hiroya, Ishikawa Shiro, Chinushi Masaomi, Aizawa Yoshifusa, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   72 ( 0 )   561 - 561   2008年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

    CiNii Books

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  • FRS-032 Testicular hormone accelerates the develoment and progress of dilated cardiomyopathy in an animal model(Molecular Determinants for the Development of Cardiomyopathy(M),Featured Research Session,The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

    Arimura Takuro, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   72 ( 0 )   150 - 150   2008年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 精巣ホルモンは動物モデルの拡張型心筋症の発生と進行を加速する(Testicular hormone accelerates the development and progress of dilated cardiomyopathy in an animal model)

    Arimura Takuro, Kimura Akinori

    Circulation Journal   72 ( Suppl.I )   150 - 150   2008年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • KCNQ1の複合ヘテロ接合体変異はQT延長症候群と関連する(A Compound Heterozygous Mutation in KCNQ1 Associated with Long QT Syndrome)

    Sato Akinori, Arimura Takuro, Aizawa Yoshiyasu, Ushinohama Hiroya, Ishikawa Shiro, Chinushi Masaomi, Aizawa Yoshifusa, Kimura Akinori

    Circulation Journal   72 ( Suppl.I )   561 - 561   2008年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 【筋ジストロフィー 現在と未来】分子病態と臨床 Emery-Dreifuss型筋ジストロフィー

    有村 卓朗, 木村 彰方

    Clinical Neuroscience   26 ( 2 )   175 - 177   2008年2月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • 雄ホルモンは拡張型心筋症病態を増悪させる

    有村 卓朗, 田中 弓子, 佐藤 里香, 高山 和己, 町田 登, 田中 綾, 清水 美希, 山根 義久, 木村 彰方

    動物臨床医学会年次大会プロシーディング   28回 ( 3 )   23 - 24   2007年11月

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    記述言語:日本語   出版者・発行元:動物臨床医学会  

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  • マイクロサテライトマーカーを用いたゲノムワイド関連解析により同定された心筋梗塞感受性遺伝子座MI-1の解析

    日野原 邦彦, 安波 道郎, 柴田 宏樹, 高橋 弓子[田中], 高橋 めぐみ, 有村 卓朗, 宝田 茂, 笹岡 大史, 山本 健, 猪子 英俊, 山田 芳司, 和泉 徹, 中島 敏晶, 木村 彰方

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   80回・30回   3T19 - 3   2007年11月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • MAPK signaling pathway is commonly activated in hearts of mouse models of autosomal dominant and X-linked Emery-Dreifuss muscular dystrophy

    A. Muchir, P. Pavlidis, V. Decostre, A. Herron, T. Arimura, Y. Hayashi, G. Bonne, H. Worman

    NEUROMUSCULAR DISORDERS   17 ( 9-10 )   800 - 800   2007年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

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  • FRS-065 Overexpression of Cardiac Myosin Light Chain Phosphatase Small Subunit (hHS-M21) Lead to Hypertrophic Cardiomyopathy(Heart Failure, Cardiac Remodeling and Cardiomyopathy 1, The 71st Annual Scientific Meeting of the Japanese Circulation Society)

    Arimura Takuro, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   71 ( 0 )   135 - 135   2007年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 心筋ミオシン軽鎖ホスファターゼスモールサブユニット(hHS-M21)の過剰発現は肥大型心筋症を誘導する(Overexpression of Cardiac Myosin Light Chain Phosphatase Small Subunit (hHS-M21) Lead to Hypertrophic Cardiomyopathy)

    Arimura Takuro, Kimura Akinori

    Circulation Journal   71 ( Suppl.I )   135 - 135   2007年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 家族性肥大型心筋症(FHCM)の新しい原因遺伝子座はHLA領域にマップされる

    大谷 仁志, 安波 道郎, 有村 卓朗, 寺崎 文生, 北浦 泰, 清水 賢巳, 木村 彰方

    MHC: Major Histocompatibility Complex   13 ( 2 )   97 - 97   2006年8月

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    記述言語:日本語   出版者・発行元:日本組織適合性学会  

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  • 【特発性心筋症 病因解明の最前線】特発性心筋症における心筋細胞膜蛋白,Z帯構成要素および核膜蛋白の機能異常 心筋細胞骨格蛋白異常と特発性心筋症

    有村 卓朗

    医学のあゆみ   217 ( 8 )   831 - 835   2006年5月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    特発性心筋症は元来基礎疾患をもたない原因不明の心筋疾患として定義されていたが,近年その原因の一部が遺伝子異常にあることが明らかとなった.また,それによって引き起こされる蛋白機能異常の解析によって,一見別々の機能をもつと考えられていた心筋細胞膜,Z帯および核膜における機能異常が相互に密接な連関をもち,最終的に心筋症という同一の疾患表現型をもたらすことが示唆されている.この知見を手がかりとしたさらなる分子遺伝学・生化学・分子生物学的な特発性心筋症発症機序の解明が,今後の心筋症に対する特異的治療法開発の可能性をより現実的なものにすると考えられる(著者抄録)

  • FRS-051 Identification of a Novel Disease Gene for Restrictive Cardiomyopathy(Frontier of Cardiomyopathy Research-1 (M) FRS11,Featured Research Session,The 70th Anniversary Annual Scientific Meeting of the Japanese Circulation Society)

    Arimura Takuro, Takahashi Megumi, Nunoda Shinichi, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   70 ( 0 )   124 - 124   2006年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

    CiNii Books

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  • 拘束型心筋症の新規疾患遺伝子の同定(Identification of a Novel Disease Gene for Restrictive Cardiomyopathy)

    Arimura Takuro, Takahashi Megumi, Nunoda Shinichi, Kimura Akinori

    Circulation Journal   70 ( Suppl.I )   124 - 124   2006年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • A BMP10 variant found in hypertensive dilated cardiomyopathy decreases binding to Tcap and increases extracellular secretion of BMP10

    A Kimura, N Nakano, T Arimura

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   39 ( 6 )   1007 - 1007   2005年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

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  • A BMP10 variant Thr326IIe associated with hypertensive dilated cardiomyopathy decreases binding to Tcap and increases extracellular secretion

    N Nakano, H Hori, T Arimura, H Shibata, T Izumi, H Tsutsui, M Yasunami, A Kimura

    CIRCULATION   112 ( 17 )   U411 - U411   2005年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Web of Science

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  • 不整脈を合併する輸送欠陥HCN43変異であるD553Nの機能的特性(Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia)

    Ueda Kazuo, Nakamura Kazufumi, Hayashi Takeharu, Inagaki Natsuko, Takahashi Megumi, Arimura Takuro, Morita Hiroshi, Higashiuesato Yasushi, Hirano Yuji, Yasunami Michio, Takishita Shuichi, Yamashina Akira, Ohe Tohru, Sunamori Makoto, Hiraoka Masayasu, Kimura Akinori

    心電図   25 ( 5 )   373 - 373   2005年9月

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    記述言語:英語   出版者・発行元:(一社)日本不整脈心電学会  

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  • Mutations in a Hyperpolarization-activated Channel as the Molecular Basis of Ventricular Arrhythmia(Arrhythmia, Basic 4 (A), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Ueda Kazuo, Hayashi Takeharu, Inagaki Natsuko, Takahashi Megumi, Aizawa Yoshiyasu, Wu Long-Mei, Nakamura Kazufumi, Higashiuesato Yasushi, Arimura Takurou, Hirano Yuji, Yasunami Michio, Sunamori Makoto, Takishita Shuichi, Ohe Tohru, Hiraoka Masayasu, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   69 ( 0 )   272 - 273   2005年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • LMNA H222P KI Mice Show Dilated Cardiomyopathy Reminiscent of the Human Cardiac Involvement of Laminopathies(Cardiomyopathy, Basic (M), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Arimura Takuro

    Circulation journal : official journal of the Japanese Circulation Society   69 ( 0 )   195 - 195   2005年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • OJ-504 Functional alterations of TCAP mutations found in hypertrophic cardiomyopathy and dilated cardiomyopathy(Cardiomyopathy, Basic (M) : OJ62)(Oral Presentation (Japanese))

    Hayashi Takeharu, Arimura Takuro, Itoh Nanatsu, Ueda Kazuo, Hohda Shigeru, Takahashi Megumi, Inagaki Natsuko, Yasunami Michio, Koga Yoshinori, Nakamura Hiroshi, Matsuzaki Masunori, Park Jeong Euy, Knoll Ralph, Hoshijima Masahiko, Chien Kenneth R, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   68 ( 0 )   352 - 353   2004年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • OJ-447 Heart-specific growth factor-like gene may be involved in the development of hypertensive heart disease.(Heart Failure, Basic 3 (M) : OJ54)(Oral Presentation (Japanese))

    Nakano Noritsugu, Arimura Takuro, Hayashi Takeharu, sawabe motoji, chida kohji, nakahara kennichi, yasunami michio, kimura akinori

    Circulation journal : official journal of the Japanese Circulation Society   68 ( 0 )   338 - 338   2004年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 非遺伝毒性肝発癌物質により長期処理したラット肝臓において発現変化を示す遺伝子の分子プロファイリング(Molecular profiling of genes showing altered expression in the livers of rats treated with non-genotoxic hepatocarcinogens for long-term)

    Shibutani Makoto, Inoue Hiroko, Takagi Hironori, Kato Natsumi, Lee Kyoung-Youl, Arimura Takuro, Uneyama Chikako, Takigami Shu, Hirose Masao

    The Journal of Toxicological Sciences   28 ( 4 )   349 - 349   2003年10月

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    記述言語:英語   出版者・発行元:(一社)日本毒性学会  

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  • Microarray-Based Identification of Three Candidate Genes for Human Heart Failure : From Dahl Rat Model to Human Genome

    Nakano Noritsugu, Arimura Takuro, Hayashi Takeharu, Yasunami Michio, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   67 ( 0 )   197 - 197   2003年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • A Novel Disease Genes for Cardiomyopathy : Identification of a CAV3 Mutation and Its Functional Alteration

    Hayashi Takeharu, Arimura Takurou, Koga Yoshinori, Ueda Kazuo, Hohda Shigeru, Takahashi Megumi, Matsumoto Yuji, Nakano Noritsugu, Inagaki Natsuko, Aizawa Yoshiyasu, Yasunami Michio, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   67 ( 0 )   319 - 319   2003年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 非遺伝子傷害性肝発がん物質長期間投与によって発現の変化する遺伝子群のカタログ化

    井上 弘子, 渋谷 淳, 高木 広憲, 加藤 奈津美, 李 京烈, 有村 卓朗, 畝山 智香子, 藤田 春香, 広瀬 雅雄

    日本毒性病理学会講演要旨集   19回   47 - 47   2002年12月

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    記述言語:日本語   出版者・発行元:日本毒性病理学会  

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  • 非遺伝子傷害性肝発がん物質投与ラットにおける発現遺伝子群のプロファイリング

    渋谷 淳, 有村 卓朗, 畝山 智香子, 高木 広憲, 広瀬 雅雄

    日本癌学会総会記事   61回   219 - 219   2002年10月

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    記述言語:日本語   出版者・発行元:日本癌学会  

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  • メタカーン固定・パラフィン包埋切片からの多目的な遺伝子解析(第四報)

    畝山 智香子, 渋谷 淳, 高木 広憲, 有村 卓朗, 広瀬 雅雄

    日本癌学会総会記事   61回   411 - 411   2002年10月

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    記述言語:日本語   出版者・発行元:日本癌学会  

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  • Alteration of gonadotropin-immunoreactive cell numbers in pituitary anterior lobe of rat offspring perinatally exposed to endocrine disrupting chemicals.(GENERAL SESSION BY POSTER PRESENTATION)(ENDOCRINE SYSTEM)

    MASUTOMI NAOYA, SHIBUTANI MAKOTO, TAKAGI HIRONORI, UNEYAMA CHIKAKO, TAKAHASHI NORIYUKI, ARIMURA TAKUROU, HIROSE MASAO

    Journal of toxicological sciences   27 ( 4 )   397 - 397   2002年10月

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    記述言語:英語   出版者・発行元:日本毒性学会  

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  • Novel HERG mutations in long QT syndrome in Japan

    Ueda Kazuo, Hoda Shigeru, Hayashi Takeharu, Arimura Takurou, Takahashi Megumi, Matsumoto Yuji, Nakano Noritsugu, Yasunami Michio, Kimura Akinori, Sunamori Makoto, Hiraoka Masayasu

    Circulation journal : official journal of the Japanese Circulation Society   66 ( 0 )   687 - 687   2002年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Genetic risk factors for myocardial infarction in Japanese

    Hoda Shigeru, Matsumoto Yuji, Nakano Noritsugu, Hayashi Takeharu, Ueda Kazuo, Arimura Takuro, Takahashi Megumi, Yasunami Michio, Kimura Akinori, Sasaoka Taishi, Izumi Toru

    Circulation journal : official journal of the Japanese Circulation Society   66 ( 0 )   435 - 435   2002年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Identification of caveolin-3 mutation in familial cardiomyopathy

    Hayashi Takeharu, Arimura Takuro, Ueda Kazuo, Hoda Shigeru, Takahashi Megumi, Matsumoto Yuji, Nakano Noritsugu, Yasunami Michio, Kimura Akinori, Koga Yoshinori

    Circulation journal : official journal of the Japanese Circulation Society   66 ( 0 )   321 - 321   2002年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Mutation of ZASP causes alteration in the affinity to protein kinase C subtypes and associates with familial dilated cardiomyopathy

    Arimura Takuro, Hayashi Takeharu, Takahashi Megumi, Ueda Kazuo, Hohda Shigeru, Yasunami Michio, Kimura Akinori

    Circulation journal : official journal of the Japanese Circulation Society   66 ( 0 )   321 - 321   2002年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Toxicogenomics 環境化学物質の生体影響評価におけるゲノム情報の活用 発がん性検出のためのToxicogenomics ラットにおける非遺伝子傷害性肝発がん物質投与による発現遺伝子のプロファイリング

    渋谷 淳, 高橋 則行, 有村 卓朗, 広瀬 雅雄

    日本薬学会年会要旨集   122年会 ( 1 )   186 - 186   2002年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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  • ヒトの特発性心筋症の遺伝子解析

    有村 卓朗, 木村 彰方

    動物の循環器 = Advances in animal cardiology   34 ( 2 )   57 - 66   2001年12月

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    記述言語:日本語   出版者・発行元:獣医循環器研究会  

    DOI: 10.11276/jsvc.34.57

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    その他リンク: http://search.jamas.or.jp/link/ui/2002176740

  • 心臓特異性ミオシン軽鎖フォスファターゼ小サブユニットの同定と筋収縮におけるその機能上の役割(Identification of heart-specific myosin light chain phosphatase small subunit and its functional role in muscle contraction)

    Arimura Takuro, Kimura Akinori, Suematsu Nobuhiro, Satoh Shinji, Takeshita Akira, Nishimura Junji, Kanaide Hideo

    Japanese Circulation Journal   65 ( Suppl.I-A )   161 - 161   2001年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 家族性肥大性心筋症と関連するTelethonin遺伝子における変異(Mutaion in the Telethonin gene associated with familial hypertrophic cardiomyopathy)

    Hayashi Takeharu, Itoh Manatsu, Arimura Takuro, Ueda Kazuo, Hohda Shigeru, Nouchi Tatsuhito, Takahashi Megumi, Kimura Akinori, Nakamura Hiroshi, Matsuzaki Masunori

    Japanese Circulation Journal   65 ( Suppl.I-A )   161 - 161   2001年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 0517 心筋特異的に発現するmyosin phosphatase調節サブユニットM21の幸三と機能の解析

    有村 卓朗, 木村 彰方, 西村 淳二, 金出 英夫, 末松 延裕, 佐藤 真司, 竹下 彰

    Japanese circulation journal   64 ( 0 )   314 - 314   2000年3月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 0530 突発性拡張型心筋症におけるタイチン遺伝子変異

    佐藤 真夏, 赤井 潤, 有村 卓朗, 高橋 めぐみ, 木村 彰方, 西 宏文, 小柳 毅, 古賀 義則, 今泉 勉

    Japanese circulation journal   64 ( 0 )   318 - 318   2000年3月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • MICA遺伝子多型の解析 新たなMICA遺伝子アリルの発見と日本人集団における対立遺伝子頻度

    大渕 信久, 高橋 めぐみ, 有村 卓朗, 木村 彰方

    MHC: Major Histocompatibility Complex   6 ( 1 )   85 - 85   1999年6月

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    記述言語:日本語   出版者・発行元:日本組織適合性学会  

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  • 0345 高安動脈炎とMICA遺伝子多型

    大渕 信久, 木村 彰方, 高橋 めぐみ, 有村 卓朗, 小林 靖, 沼野 藤夫

    Japanese circulation journal   63 ( 1 )   234 - 234   1999年3月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 1045 タイチンZリピート領域のゲノム構造と家族性拡張型心筋症における変異

    佐藤 真夏, 高橋 めぐみ, 有村 卓朗, 大渕 信久, 中村 剛之, 木村 彰方, 西 宏文

    Japanese circulation journal   63 ( 1 )   412 - 412   1999年3月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 0556 心筋特異的に発現するヒトnebuletteのcDNAおよびゲノム構造の決定と拡張型心筋症患者における遺伝子解析

    有村 卓朗, 中村 剛之, 広井 知歳, 高橋 めぐみ, 佐藤 真夏, 大渕 信久, 木村 彰方

    Japanese circulation journal   63 ( 1 )   288 - 288   1999年3月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 僧帽弁閉鎖不全症罹患犬にみられた血栓性塞栓症による貫壁性心筋梗塞の1例

    関 慶久, 町田 登, 有村 卓朗

    The Journal of Veterinary Medical Science   60 ( 6 )   741 - 743   1998年6月

  • 0638 拡張型心筋症の遺伝子解析 : 心筋ザルコメアZ帯構成遺伝子群(タイチン、ジストロフィン、メタビンキュリン、MLP)変異の検索

    佐藤 真夏, 有村 卓朗, 高橋 めぐみ, 大渕 信久, 中村 剛之, 笹岡 大史, 広井 知歳, 木村 彰方

    Japanese circulation journal   62 ( 0 )   264 - 264   1998年2月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 1052 心筋に強く発現する未知の遺伝子群の単離とその構造解析

    中村 剛之, 有村 卓朗, 広井 知歳, 佐藤 真夏, 木村 彰方

    Japanese circulation journal   62 ( 0 )   368 - 368   1998年2月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 0725 Platelet/Endothelial Cell Adhesion Molecule-1(PECAM-1)遺伝子多型は心筋梗塞のGenetic Risk Factorである

    笹岡 大史, 有村 卓朗, 高橋 めぐみ, 大渕 信久, 中村 剛之, 佐藤 真夏, 広井 知歳, 木村 彰方

    Japanese circulation journal   62 ( 0 )   286 - 286   1998年2月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • 0640 MnSOD遺伝子のリーダー配列内多型は、ミトコンドリア内への移行効率の相違を介して孤発性拡張型心筋症への感受性を規定する

    広井 知歳, 有村 卓朗, 高橋 めぐみ, 原田 晴仁, 木村 彰方

    Japanese circulation journal   62 ( 0 )   265 - 265   1998年2月

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    記述言語:日本語   出版者・発行元:社団法人日本循環器学会  

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  • Frequency and geographic distribution of mutations in the HCM genes found in Oriental familial hypertrophic cardiomyopathy [abstract]

    KIMURA A., Harada Haruhito, Satoh Manatsu, Hiroi Shitoshi, Sasaoka Taishi, Takahashi Megumi, Nakamura Takeyuki, Ohbuchi Nobuhisa, Arimura Takurou

    Japanese Circulation Journal   62 ( 0 )   IS034   1998年

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 弁膜症罹患犬の僧帽弁における酸性ムコ多糖類の生化学的検索

    有村 卓朗

    日本獣医学会学術集会講演要旨集   123回   106 - 106   1997年3月

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    記述言語:日本語   出版者・発行元:(公社)日本獣医学会  

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  • イヌの僧帽弁閉鎖不全症における弁膜のコラーゲン型の生化学的解析

    有村 卓朗

    日本獣医学会学術集会講演要旨集   121回   86 - 86   1996年4月

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    記述言語:日本語   出版者・発行元:(公社)日本獣医学会  

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▼全件表示

共同研究・競争的資金等の研究

  • 心臓拡張機能制御の解明および生体内拡張機能可視化の確立

    研究課題/領域番号:24390201  2012年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    牧野 伸司, 山岸 敬幸, 有村 卓朗

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    拡張不全の予後を改善する治療方法はない。我々はメダカ変異体スクリーニングから、心臓拡張機能異常を示す突然変異体を樹立した。ポジショナルクローニング法により、メダカ変異体はTitin遺伝子(TTN)に点変異があることを発見した。変異部位はMuscle Ring Finger (MURF) 結合部位であった。メダカ変異体ではTTNとMURF結合増強により、柔軟なTTN isoformのユビキチン化による分解で、固いTTN isoformへの変化が観察された。メダカ拡張不全変異体と拡張不全を示す家族性心筋症のを用いて、TTNとMURF結合・解離による拡張不全発症の機序解明を行った。

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  • 体系的遺伝子変異解析に立脚した心不全病態の包括的解明

    研究課題/領域番号:24790335  2012年4月 - 2013年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    有村 卓朗

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    研究代表者は以前、肥大型心筋症(HCM)患者においてANKRD1遺伝子内に3種の変異を同定したが、これらの変異が心筋収縮に与える影響は不明であった。そこでCARP変異を単離心筋に導入後、三次元再構築による筋収縮ユニット(EHTs)を形成し、その筋収縮力測定などを行うことで心筋収縮・弛緩パラメーターへの病因変異の影響を検討した。その結果、3種の変異のうちT123M変異のみが心筋の収縮力を亢進することが判明した。次いで、EHTs内における各変異タンパクの分布を検討したところ、P52A変異やI280V変異存在下ではANKRD1タンパクがサルコメアにほとんど取り込まれていない一方、EHTsにプロテアゾーム阻害剤処理を施した場合には、P52A変異やI280V変異の存在下でもANKRD1タンパクはサルコメアに取り込まれており、またI280V変異特異的に心筋弛緩時間が延長することが明らかとなった。これらの結果は、ANKRD1変異による心筋収縮パラメーターへの影響が変異ごとに異なっていることを示している。
    一方、これまでに代表者が拡張型心筋症(DCM)モデルとして作製し、その表現型に性差が存在するラミンA/C点変異(LmnaH222P/H222P)マウスにおける先行研究の結果から、雄性ホルモン(アンドロゲン)が心不全病態の発症・進展に深く関与していることが示唆されていた。さらに本研究ではラミンA/C変異(R225X)保有DCM患者およびLmnaH222P/H222Pマウス心臓内ではアンドロゲン受容体(AR)の細胞核内移行が亢進しており、この核内へのARの蓄積は心筋特異的に発現するFHL2を仲立ちとして、転写因子SRFの核内移行を随伴していることが明らかとなった。このことは心筋細胞におけるARの発現性がDCMの性差と密接に関連することを示している。

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  • Molecular pathogenic analysis of the striated muscle laminopathies

    2011年

    Association Française contre les Myopathies  Research grant 

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  • ゲノム医科学的アプローチによる特発性心筋症病態形成メカニズムの解明

    研究課題/領域番号:20790520  2008年 - 2009年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    有村 卓朗

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    特発性心筋症は難治性心不全を来たす心筋原発性疾患である。本研究では、特発性心筋症の新規病態形成メカニズムの解明を目的として、非心筋収縮調節要素異常と特発性心筋症との関わりについて解析を行い、その結果として(1)新規拡張型心筋症原因遺伝子としてCARP(ANKRD1)およびフクチン(FKTN)を同定し、(2)ZASP/Cypher内の拡張型心筋症病因変異によるPGM1タンパクの細胞内動態変化がその病態と深く関わっていることを解明した。

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  • 心筋ミオシン軽鎖リン酸化制御に基づく心不全新規治療戦略

    2007年

    (財)日本心臓財団  研究奨励金 

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  • 心不全病態形成機構の解明と心筋ミオシン軽鎖リン酸化制御に基づく新規治療法の開発

    研究課題/領域番号:18790492  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    有村 卓朗

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    配分額:3400000円 ( 直接経費:3400000円 )

    遺伝性心不全の病因ゲノムとその病態形成機構を解明するため、前年度に心筋症原因遺伝子として同定したミオパラディンと結合能を持つCARP遺伝子における遺伝子変異を特発性心筋症患者集団において検索した結果、3名の患者にそれぞれ独立した点変異を特定し、その機能解析の結果、それらの変異存在下においてミオパラディンとの結合性が有意に上昇することが明らかとなった。またCARP遺伝子を新生児ラット心筋初代培養細胞へ発現させ、その細胞内局在について検討した結果、野生型と比較して変異体では核内への局在が上昇していた。さらにCARPと結合能を持つタイチンN2A領域についても特発性心筋症患者集団を用いた遺伝子変異解析を行った結果、2つの点変異を特定し、これらの変異の存在下でも同様にCARPとの結合性が有意に増強されることが明らかとなった。
    一方、前年度までに作製に成功したhHS-M21遺伝子トランスジェニックマウス心臓について、心エコーならびに心電図測定による詳細な表現型解析を行い、最もhHS-M21発現量の高い1系統においては4ケ月齢時以降に洞性不整脈を伴う拡張型心筋症を呈し、12ケ月齢までに全ての個体が心不全死することが明らかとなった。またAffymetrix GeneChip^<[○!R]>を用いたhHS-M21トランスジェニックマウス心臓内遺伝子発現の網羅的な解析により、3124遺伝子(発現上昇3000遺伝子、発現減少124遺伝子)の発現の変化を確認し、このうち有意な発現変化を示すものとして、ギャップ結合、アクチン細胞骨格および接着斑などのタンパクをコードする遺伝子群を同定した。さらにウエスタンブロット法を用いてhHS-M21周辺タンパクのリン酸化について検討した結果、hHS-M21結合蛋白であるMYPTsの696Thrのリン酸化の程度が有意に上昇していることが明らかとなった。

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  • 心不全病態形成機構の解明と心筋ストレッチ反応是正に基づく新規治療法開発

    2006年

    独立行政法人医薬基盤研究所  保健医療分野における基礎研究推進事業 

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  • Pathogenic analysis and development of therapeutic strategy for the striated muscle laminopathies

    2006年

    Association Française contre les Myopathies  Research grant 

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  • 特発性拡張型心筋症の病因解明と新規病態診断法の開発に関する研究

    2005年

    (財)黒住医学研究振興財団  研究助成金 

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  • 特発性心筋症の病態形成メカニズムの解明と心筋ミオシン軽鎖リン酸化制御に基づく新規治療法の開発

    2005年

    (財)持田記念医学薬学振興財団  研究助成金 

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  • 心筋ミオシン軽鎖リン酸化制御に基づく新規心不全治療法の開発

    2005年

    財)先進医薬研究振興財団  循環医学萌芽研究助成金 

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  • 心不全に伴う心臓伝達障害発症機序の検討

    2005年

    (財)福田記念医療技術振興財団  研究助成金 

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  • Nuclear Envelope and Muscle Disease

    2002年

    Human Frontiers Science Program  リサーチフェロー 

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