2021/05/24 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

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 / 循環器内科学

  • ライフサイエンス / 医化学

  • ライフサイエンス / 獣医学

学歴

  • 東京医科歯科大学   大学院 医学系研究科

    1997年4月 - 2001年3月

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    国名: 日本国

  • 東京農工大学   農学部   獣医学科

    1991年4月 - 1997年3月

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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

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. .  Cardiovasc Res117 ( 4 ) 1118 - 1131   2021年4月査読

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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  

    BACKGROUND: During heart failure, the levels of circulatory HSPD1 (HSP60) increase. However, its underlying mechanism is still unknown. The apical domain of 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 edema 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 atrioventricular block and sudden death at eight months 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 WT, nbl-type, and DCM-type HSPD1, with tetracycline-dependent expression. Compared to WT, 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. CONCLUSIONS: Mutations in HSPD1 caused mitochondrial dysfunction and induced mitophagy. Mitochondrial dysfunction caused increased ROS and cardiac atrophy. TRANSLATIONAL PERSPECTIVE: The aged heart is more susceptible to stress despite the increased compensatory chaperones/co-chaperones activity. Here, we identified a point mutation in HSPD1 in a human DCM family. Using zebrafish, we demonstrated that functional inactivation of HSPD1 resulted in increased ROS level and mitophagy, thereby resulting in heart failure at a relatively early age. Inhibition of ROS activity by antioxidants decreased cell death and mitophagy. This work identifies the key role of HSPD1 in cardiac muscle protection and suggests the supplementation of antioxidants may improve the cardiac function through the mitochondrial ROS pathway in patients with chronic heart failure.

    DOI: 10.1093/cvr/cvaa158

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  • Higashikuse Y, Mittal N, Arimura T, Yoon SH, 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. .  Dis Model Mech12 ( 11 ) dmm041103 - dmm041103   2019年11月査読

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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 cardiovascular-mutant 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 M-line-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 CK, Zhan DY, 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. .  Am J Physiol Heart Circ Physiol314 ( 6 ) H1192 - H1202   2018年6月査読

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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 Ca(2+) sensitivity of muscle contraction. We have previously shown that a heart-specific myosin light chain phosphatase small subunit (hHS-M21) increases the Ca(2+) 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 Ca(2+) sensitivity in cardiomyopathy. We generated transgenic mice with cardiac-specific overexpression of hHS-M21. We confirmed that hHS-M21 increased the Ca(2+) 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 phosphorylation-dependent 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 SI, Takakuwa Y, Ueda A, Inada KI, Sarai M, Arimura T, Mutoh T, Kimura A, Ozaki Y .  Hypertrophic Cardiomyopathy Accompanied by Spinocerebellar Atrophy With a Novel Mutation in Troponin I Gene. .  Int Heart J57 ( 4 ) 507 - 510   2016年7月査読

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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:一般社団法人 インターナショナル・ハート・ジャーナル刊行会  

    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. .  Eur Heart J37 ( 18 ) 1469 - 1475   2016年5月査読

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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 TK, 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. .  J Hum Genet60 ( 10 ) 641 - 645   2015年10月査読

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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:Nature Publishing Group  

    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 T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N .  Novel mutation in the alpha-myosin heavy chain gene is associated with sick sinus syndrome. .  Circ Arrhythm Electrophysiol8 ( 2 ) 400 - 408   2015年4月査読

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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.  

    BACKGROUND: Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding alpha-myosin heavy chain (alpha-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 alpha-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 alpha-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 alpha-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 alpha-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type alpha-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 alpha-MHC but not by delE933 alpha-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. .  J Am Heart Assoc3 ( 6 ) e001263 - e001263   2014年12月査読

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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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  • Okada S, Suzuki Y, Arimura T, Kimura A, Narumi H, Hasegawa S .  A novel de novo mutation of beta-cardiac myosin heavy chain gene found in a twelve-year-old boy with hypertrophic cardiomyopathy. .  J Genet93 ( 2 ) 557 - 560   2014年8月査読

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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 Genetics  

    DOI: 10.1007/s12041-014-0414-8

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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. .  Circ J77 ( 12 ) 2990 - 2996   2013年12月査読

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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:一般社団法人 日本循環器学会  

    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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  • 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. .  J Autoimmun47   25 - 33   2013年12月査読

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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 kappaB-like protein (IkappaBL), 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 IkappaBL 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 IkappaBL 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 IkappaBL was independent from the kinase activity of CLK1. On the other hand, it was demonstrated that an SR protein, ASF/SF2, bound both IkappaBL and CLK1 at the RNA-recognition motifs of ASF/SF2, implying a competition of IkappaBL and CLK1 on SR protein. In addition, IkappaBL 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 IkappaBL 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.

    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 AT, 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. .  Cardiovasc Res99 ( 3 ) 382 - 394   2013年8月査読

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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 from the 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 Res Cardiol108 ( 3 ) 349 - 349   2013年5月査読

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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.

    DOI: 10.1007/s00395-013-0349-x

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  • Ishikawa T, Takahashi N, Ohno S, Sakurada H, Nakamura K, On YK, Park JE, 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. .  Circ J77 ( 4 ) 959 - 967   2013年4月査読

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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:一般社団法人 日本循環器学会  

    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, Navbeta3, 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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  • Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, Schwartz PJ, On YK, Park JE, 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. .  Circ Arrhythm Electrophysiol5 ( 6 ) 1098 - 1107   2012年12月査読

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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 alpha-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.

    DOI: 10.1161/CIRCEP.111.969972

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  • Sato A, Sakamoto N, Ando K, Kaneshiro T, Uekita H, Sugimoto K, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh S, Sato M, Tamagawa K, Arimura T, Kimura A, Takeishi Y .  Dilated phase of hypertrophic cardiomyopathy caused by two different sarcomere mutations, treated with surgical left ventricular reconstruction and cardiac resynchronization therapy with a defibrillator. .  Intern Med51 ( 18 ) 2559 - 2564   2012年9月査読

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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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  • Purevjav E, Arimura T, Augustin S, Huby AC, Takagi K, Nunoda S, Kearney DL, Taylor MD, Terasaki F, Bos JM, Ommen SR, Shibata H, Takahashi M, Itoh-Satoh M, McKenna WJ, Murphy RT, Labeit S, Yamanaka Y, Machida N, Park JE, Alexander PM, Weintraub RG, Kitaura Y, Ackerman MJ, Kimura A, Towbin JA .  Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. .  Hum Mol Genet21 ( 9 ) 2039 - 2053   2012年5月査読

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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 alpha-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.

    DOI: 10.1093/hmg/dds022

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  • Bertrand AT, Renou L, Papadopoulos A, Beuvin M, Lacene E, Massart C, Ottolenghi C, Decostre V, Maron S, Schlossarek S, Cattin ME, 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. .  Hum Mol Genet21 ( 5 ) 1037 - 1048   2012年3月査読

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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(DeltaK32) knock-in mouse harboring a L-CMD mutation. Lmna(DeltaK32/DeltaK32) 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(DeltaK32/DeltaK32), 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 DeltaK32-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.

    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 YL, Fukuda K, Sasaoka T, Izumi T, Ashizawa N, Kimura A .  Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. .  Circ J76 ( 2 ) 453 - 461   2012年2月査読

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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:一般社団法人 日本循環器学会  

    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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  • 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. .  Hum Mutat32 ( 12 ) 1481 - 1491   2011年12月査読

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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.

    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 YL .  Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy. .  Circ J75 ( 11 ) 2654 - 2659   2011年11月査読

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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:一般社団法人 日本循環器学会  

    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 beta-myosin heavy chain gene [MYH7], cardiac myosin-binding protein C gene [MYBPC3], cardiac troponin T gene [TNNT2], alpha-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. .  J Biol Chem285 ( 44 ) 33680 - 33690   2010年10月査読

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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-M(21)) that increased the sensitivity to Ca(2+) in muscle contraction. In this study, we investigated the role of hHS-M(21) in the regulation of MLCP phosphorylation. Two isoforms of hHS-M(21), hHS-M(21)A and hHS-M(21)B, 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-M(21). The hHS-M(21) 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-M(21) bound ROCK and enhanced the ROCK activity. These findings suggest that hHS-M(21) is a heart-specific effector of ROCK and plays a regulatory role in the MYPT1 phosphorylation at Thr-696 by ROCK.

    DOI: 10.1074/jbc.M110.122390

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  • Purevjav E, Varela J, Morgado M, Kearney DL, Li H, Taylor MD, Arimura T, Moncman CL, McKenna W, Murphy RT, Labeit S, Vatta M, Bowles NE, Kimura A, Boriek AM, Towbin JA .  Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. .  J Am Coll Cardiol56 ( 18 ) 1493 - 1502   2010年10月査読

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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.

    DOI: 10.1016/j.jacc.2010.05.045

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  • Arimura T, Sato R, Machida N, Bando H, Zhan DY, 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. .  J Am Coll Cardiol55 ( 14 ) 1503 - 1505   2010年4月査読

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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  

    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. .  Biochim Biophys Acta1800 ( 1 ) 31 - 39   2010年1月査読

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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.

    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. .  J Biol Chem284 ( 50 ) 35122 - 35133   2009年12月査読

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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 (R(633)GR and R(646)LR). 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.

    DOI: 10.1074/jbc.M109.017293

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  • Hinohara K, Nakajima T, Yasunami M, Houda S, Sasaoka T, Yamamoto K, Lee BS, Shibata H, Tanaka-Takahashi Y, Takahashi M, Arimura T, Sato A, Naruse T, Ban J, Inoko H, Yamada Y, Sawabe M, Park JE, Izumi T, Kimura A .  Megakaryoblastic leukemia factor-1 gene in the susceptibility to coronary artery disease. .  Hum Genet126 ( 4 ) 539 - 547   2009年10月査読

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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.

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  • Park YE, Hayashi YK, Bonne G, Arimura T, Noguchi S, Nonaka I, Nishino I .  Autophagic degradation of nuclear components in mammalian cells. .  Autophagy5 ( 6 ) 795 - 804   2009年8月査読

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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:Autophagy  

    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.

    DOI: 10.4161/auto.8901

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  • Arimura T, Bos JM, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Moulik M, Doi YL, Towbin JA, Ackerman MJ, Kimura A .  Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy. .  J Am Coll Cardiol54 ( 4 ) 334 - 342   2009年7月査読

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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.

    DOI: 10.1016/j.jacc.2008.12.082

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  • Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek Aladin M, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA .  ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. .  J Am Coll Cardiol54 ( 4 ) 325 - 333   2009年7月査読

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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.

    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 JA, Chikamori T, Yamashina A, Kimura A .  Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. .  Cardiovasc Res83 ( 1 ) 80 - 88   2009年7月査読

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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.

    DOI: 10.1093/cvr/cvp119

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  • Arimura T, Hayashi YK, 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. .  Circ J73 ( 1 ) 158 - 161   2009年1月査読

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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:社団法人日本循環器学会  

    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, Chida K, Sawabe M, Arimura T, Sato A, Lee BS, Ban JM, Yasunami M, Park JE, Izumi T, Kimura A .  Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. .  J Hum Genet53 ( 4 ) 357 - 359   2008年4月査読

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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:Springer Japan  

    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.

    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

  • Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A .  Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy. .  Am J Physiol Heart Circ Physiol293 ( 6 ) H3396 - H3403   2007年12月査読

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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  

    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.

    DOI: 10.1152/ajpheart.00311.2007

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  • Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A .  Structural analysis of obscurin gene in hypertrophic cardiomyopathy. .  Biochem Biophys Res Commun362 ( 2 ) 281 - 287   2007年10月査読

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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:Biochemical and Biophysical Research Communications  

    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.

    DOI: 10.1016/j.bbrc.2007.07.183

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  • Ben Yaou R, Toutain A, Arimura T, Demay L, Massart C, Peccate C, Muchir A, Llense S, Deburgrave N, Leturcq F, Litim K E, Rahmoun-Chiali N, Richard P, Babuty D, Recan-Budiartha D, Bonne G .  Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism? .  Neurology68 ( 22 ) 1883 - 1894   2007年5月査読

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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:Neurology  

    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.

    DOI: 10.1212/01.wnl.0000263138.57257.6a

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  • Muchir A, Pavlidis P, Decostre V, Herron AJ, Arimura T, Bonne G, Worman HJ .  Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. .  J Clin Invest117 ( 5 ) 1282 - 1293   2007年5月査読

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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 Clinical Investigation  

    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.

    DOI: 10.1172/JCI29042

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  • Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Satoh-Itoh M, Sasaoka T, Izumi T, Bonne G, Schwartz K, Kimura A .  Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy. .  Biochem Biophys Res Commun357 ( 1 ) 162 - 167   2007年5月査読

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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:Biochemical and Biophysical Research Communications  

    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.

    DOI: 10.1016/j.bbrc.2007.03.128

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  • Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A .  Alpha B-crystallin mutation in dilated cardiomyopathy. .  Biochem Biophys Res Commun342 ( 2 ) 379 - 386   2006年4月査読

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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.

    DOI: 10.1016/j.bbrc.2006.01.154

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  • Matsumoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano K, Kimura A .  Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy. .  J Muscle Res Cell Motil26 ( 6-8 ) 367 - 374   2005年12月査読

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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 Muscle Research and Cell Motility  

    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.

    DOI: 10.1007/s10974-005-9018-5

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  • Arimura T, Helbling-Leclerc A, Massart C, Varnous S, Niel F, Lacene E, Fromes Y, Toussaint M, Mura AM, Keller DI, Amthor H, Isnard R, Malissen M, Schwartz K, Bonne G .  Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. .  Hum Mol Genet14 ( 1 ) 155 - 169   2005年1月査読

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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  

    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.

    DOI: 10.1093/hmg/ddi017

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  • Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A .  Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. .  J Am Coll Cardiol44 ( 11 ) 2192 - 2201   2004年12月査読

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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 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.

    DOI: 10.1016/j.jacc.2004.08.058

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  • Muchir A, Medioni J, Laluc M, Massart C, Arimura T, van der Kooi AJ, Desguerre I, Mayer M, Ferrer X, Briault S, Hirano M, Worman HJ, Mallet A, Wehnert M, Schwartz K, Bonne G .  Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. .  Muscle Nerve30 ( 4 ) 444 - 450   2004年10月査読

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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:Muscle and Nerve  

    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.

    DOI: 10.1002/mus.20122

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  • Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A .  Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. .  J Biol Chem279 ( 26 ) 27194 - 27198   2004年6月査読

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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  

    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.

    DOI: 10.1074/jbc.M311953200,

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  • Lee KY, Shibutani M, Takagi H, Arimura T, Takigami S, Uneyama C, Kato N, Hirose M .  Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats. .  Food Chem Toxicol42 ( 4 ) 687 - 695   2004年4月査読

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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:Food and Chemical Toxicology  

    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.

    DOI: 10.1016/j.fct.2003.12.005,

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  • Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi M, Ueda K, Nouchi T, Hohda S, Shibutani M, Hirose M, Chen J, Park JE, Yasunami M, Hayashi H, Kimura A .  A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C. .  J Biol Chem279 ( 8 ) 6746 - 6752   2004年2月査読

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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  

    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.

    DOI: 10.1074/jbc.M311849200,

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    PubMed

  • Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A .  Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. .  Biochem Biophys Res Commun313 ( 1 ) 178 - 184   2004年1月査読

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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:Biochemical and Biophysical Research Communications  

    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.

    DOI: 10.1016/j.bbrc.2003.11.101

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    PubMed

  • Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A .  Titin mutations as the molecular basis for dilated cardiomyopathy. .  Biochem Biophys Res Commun291 ( 2 ) 385 - 393   2002年2月査読

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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:Biochemical and Biophysical Research Communications  

    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.

    DOI: 10.1006/bbrc.2002.6448,

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    PubMed

  • Obuchi N, Takahashi M, Nouchi T, Satoh M, Arimura T, Ueda K, Akai J, Ota M, Naruse T, Inoko H, Numano F, Kimura A .  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 - 535   2001年6月査読

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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.

    PubMed

  • Kimura A, Ito-Satoh M, Hayashi T, Takahashi M, Arimura T .  Molecular etiology of idiopathic cardiomyopathy in Asian populations. .  J Cardiol37 Suppl 1 ( Suppl.I ) 139 - 146   2001年6月査読

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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.

    PubMed

    CiNii Article

    CiNii Books

  • Arimura T, Suematsu N, Zhou Y B, Nishimura J, Satoh S, Takeshita A, Kanaide H, Kimura A .  Identification, characterization, and functional analysis of heart-specific myosin light chain phosphatase small subunit. .  J Biol Chem276 ( 9 ) 6073 - 6082   2001年3月査読

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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.

    DOI: 10.1074/jbc.M008566200,

    PubMed

  • Arimura T, Nakamura T, Hiroi S, Satoh M, Takahashi M, Ohbuchi N, Ueda K, Nouchi T, Yamaguchi N, Akai J, Matsumori A, Sasayama S, Kimura A .  Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy. .  Hum Genet107 ( 5 ) 440 - 451   2000年11月査読

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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.

    PubMed

  • Kimura A, Kobayashi Y, Takahashi M, Ohbuchi N, Kitamura H, Nakamura T, Satoh M, Sasaoka T, Hiroi S, Arimura T, Akai J, Aerbajinai W, Yasukochi Y, Numano F .  MICA gene polymorphism in Takayasu's arteritis and Buerger's disease. .  Int J Cardiol66 Suppl 1   S107 - 13; discussion S115   1998年10月査読

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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.

    PubMed

  • Machida N, Arimura T, Otagiri Y, Kiryu K, Oka T .  Epithelioid haemangioendothelioma of the lung in a dog. .  J Comp Pathol119 ( 3 ) 317 - 322   1998年10月査読

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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.

    PubMed

  • Seki Y, Machida N, Arimura T, Kiryu K, Kondoh M .  Transmural myocardial infarction caused by thromboembolism associated with mitral insufficiency in a dog. .  J Vet Med Sci60 ( 6 ) 741 - 743   1998年6月査読

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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:社団法人日本獣医学会  

    A 10-year-old dog, which had been treated for mitral insufficiency, died suddenly. Transmural myocardial infarction secondary to thromboembolic occlusion of the subsinuosal interventricular branch of the left circumflex artery was noted in the posterior lower half of the left ventricular wall, involving the interventricular septum and a part of right ventricular wall. The mitral valve leaflets were markedly thickened (valvular endocardiosis). These were a patchy area of jet lesion and several mural thrombi on the left-atrial endocardium. The embolus in the subsinuosal interventricular branch was composed of mostly platelets and fibrin, showing the same histologic features as those of the mural thrombi on the left-atrial endocardium. From these findings, it was concluded that dislodgement of part of the mural thrombi on the left-atrial endocardium caused thromboembolism of the subsinuosal interventricular branch.

    DOI: 10.1292/jvms.60.741

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    PubMed

    CiNii Article

    CiNii Books

    その他リンク: http://search.jamas.or.jp/link/ui/1998250648

  • Arimura T, Machida N, Nishida Y, Kiryu K .  Fatal rupture of the brachiocephalic artery in a dog. .  J Comp Pathol118 ( 2 ) 151 - 154   1998年2月査読

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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.

    PubMed

  • 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

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    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.

    PubMed

  • Arimura T. .  Molecular etiology of idiopathic cardiomyopathy .  Acta Myologica26 ( 3 ) 153 - 158   2007年12月査読

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    出版者・発行元:Acta Myologica  

    Scopus

  • Yaou R.B. .  Genetics of laminopathies .  Novartis Foundation Symposium264   81 - 90   2005年12月査読

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    出版者・発行元:Novartis Foundation Symposium  

    Scopus

  • Ben Yaou R, Muchir A, Arimura T, Massart C, Demay L, Richard P, Bonne G .  Genetics of laminopathies. .  Novartis Foundation symposium264   81 - 90; discussion 90   2005年査読

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  • Ben Yaou R. .  Genetics of laminopathies. .  Novartis Foundation symposium264   2005年査読

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    出版者・発行元:Novartis Foundation symposium  

    Scopus

  • 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

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    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.

    PubMed

  • Obuchi N. .  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 - 535   2001年9月査読

     詳細を見る

    出版者・発行元:Tissue Antigens  

    DOI: 10.1034/j.1399-0039.2001.057006520.x

    Scopus

  • Arimura T. .  Identification, Characterization, and Functional Analysis of Heart-specific Myosin Light Chain Phosphatase Small Subunit .  Journal of Biological Chemistry276 ( 9 ) 6073 - 6082   2001年3月査読

     詳細を見る

    出版者・発行元:Journal of Biological Chemistry  

    DOI: 10.1074/jbc.M008566200

    Scopus

  • Kimura A. .  Molecular etiology of idiopathic cardiomyopathy in Asian populations. .  Journal of cardiology37 Suppl 1   139 - 146   2001年査読

     詳細を見る

    出版者・発行元:Journal of cardiology  

    Scopus

  • Arimura T. .  Characterization of the human nebulette gene: A polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy .  Human Genetics107 ( 5 ) 440 - 451   2000年査読

     詳細を見る

    出版者・発行元:Human Genetics  

    DOI: 10.1007/s004390000389

    Scopus

  • Kimura A. .  MICA gene polymorphism in Takayasu's arteritis and Buerger's disease .  International Journal of Cardiology66 ( SUPPL. 1 )   1998年10月査読

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    出版者・発行元:International Journal of Cardiology  

    DOI: 10.1016/S0167-5273(98)00157-0

    Scopus

  • Machida N. .  Epithelioid haemangioendothelioma of the lung in a dog .  Journal of Comparative Pathology119 ( 3 ) 317 - 322   1998年査読

     詳細を見る

    出版者・発行元:Journal of Comparative Pathology  

    DOI: 10.1016/S0021-9975(98)80053-4

    Scopus

  • Arimura T. .  Fatal rupture of the brachiocephalic artery in a dog .  Journal of Comparative Pathology118 ( 2 ) 151 - 154   1998年査読

     詳細を見る

    出版者・発行元:Journal of Comparative Pathology  

    DOI: 10.1016/S0021-9975(98)80007-8

    Scopus

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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 

     詳細を見る

    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

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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。

  • 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。

  • Molecular pathogenic analysis of the striated muscle laminopathies

    2011年

    Association Française contre les Myopathies  Research grant 

  • 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

      詳細を見る

    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。

  • 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 

  • 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。

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

    2006年

    Association Française contre les Myopathies  Research grant 

  • 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 

  • 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 

  • 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 

  • 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)宮田心臓病研究振興基金  医学研究者の学究等に対する奨励金 

  • 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 

  • 横紋筋特異的ラミノパチーの病態形成メカニズムの解明と核膜-細胞質間ストレッチ反応制御に基づいた新規治療法の開発

    2005年

    (財)金原一郎記念医学医療振興財団  基礎医学医療研究助成金 

  • 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 

  • Nuclear Envelope and Muscle Disease

    2002年

    Human Frontiers Science Program  リサーチフェロー 

  • 高血圧性心筋症関連遺伝子群の同定

    2000年

    日本学術振興会  特別研究員奨励費 

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