Faculty Profiles - SANO Akira

Papers - SANO Akira

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Nishizawa Y., Sakimoto H., Nagata O., Sasaki N., Urata Y., Arai K., Hiwatashi H., Yokoyama I., Kishida S., Sano A., Nakamura M. . Chorein deficiency promotes ferroptosis . FEBS Open Bio15 ( 1 ) 58 - 68 2025.1Reviewed

Authorship：Lead author,　Last author,　Corresponding author Language：Japanese Publisher：FEBS Open Bio

Ferroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A deficiency in ferroptosis. The VPS13A gene encodes for chorein, and its deficiency is a molecular cause of chorea-acanthocytosis (ChAc), a Huntington-like disease with neurodegeneration in the striatum. In our previous study, we found male infertility characterized by increased malondialdehyde staining of the spermatozoa in the testes of the ChAc model mice. Thus, in this study we performed metabolome analysis of sperm extracted from the epididymis of the ChAc model mice, which revealed decreased cystine levels, suggesting an association between chorein deficiency and ferroptosis. We then investigated the role of chorein in ferroptosis using VPS13A knockdown (VPS13A-KD) HEK293 cells. We found that VPS13A-KD cells displayed a significantly diminished resistance to tert-Butyl hydroperoxide (tBHP)-induced lipid peroxidation and cell death compared to control cells, which could be rescued by treatment with ferrostatin-1. Moreover, VPS13A-KD cells showed Fe(II) accumulation, suggesting an impaired capacity for divalent iron removal. In the cytosolic fraction of VPS13A-KD cells, the protein level of glutathione peroxidase 4 (GPX4) was significantly reduced, suggesting that dysfunction of chorein impairs GPX4 transport, thereby facilitating ferroptosis. These results suggest that ferroptosis may contribute to neurodegeneration in ChAc caused by loss of chorein function.

DOI： 10.1002/2211-5463.13870

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Ishiura H, Doi K, Mitsui J, Yoshimura J, et al. . Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. . Nature Genetics50 ( 4 ) 581 - 590 2018.4Reviewed

Ueno S, Maruki Y, Nakamura M, Tomemori Y, Kamae K, Tanabe H, Yamashita Y, Matsuda S, Kaneko S and Sano A . The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis . Nature Genetics28 ( 2 ) 121 - 122 2001.6Reviewed

Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kikushima H, Umino K, Kurosawa H, Furusawa T, Nihei K, Inoue T, Sano A, Komure O, Yoshizawa T, Kanazawa I, and Yamada M . Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p . Nature Genetics6 14 - 18 1994.1Reviewed

Akira Sano . Challenges and Reform Directions for National Universities 20 Years After Incorporation . 21 ( 8 ) 24 - 28 2025.11Invited

The Role of Chorein Deficiency in Late Spermatogenesis . Biomedicines12 240 2024.1Reviewed

佐野輝 . 精神医学・医療の移ろい . 九州神経精神医学69 ( 1 ) 1 - 2 2023.12

Sakimoto H, Urata Y, Ishizuka T, Kimotsuki H, Kasugai M, Fukuhara R, Sano A, Nakamura M . Association of auditory Charles Bonnet syndrome with increased blood flow in the nondominant Brodmann area 22 . PCN Reports2 ( 2 ) e92 2023.5Reviewed International journal

Arai K., Sakimoto H., Urata Y., Kariya M., Nakamura T., Ikehata T., Shimojima R., Furue N., Ishizuka T., Sano A., Nakamura M. . Aging-Related Catatonia with Reversible Dopamine Transporter Dysfunction in Females with Depressive Symptoms: A Case Series . American Journal of Geriatric Psychiatry31 ( 12 ) 1200 - 1205 2023Reviewed

Authorship：Lead author,　Last author,　Corresponding author Language：Japanese Publisher：American Journal of Geriatric Psychiatry

Objectives: The authors describe five depressive patients with initially decreased striatal accumulation of dopamine transporter (DAT) single-photon emission computed tomography (SPECT), which improved in parallel with clinical symptoms. Methods: Patients who exhibited decreased striatal accumulation and recovery of DATSPECT were identified among patients with the symptoms of depression. Their clinical and neuroimaging data were reviewed. Results: Five patients were identified. All patients were presenile or senile women who presented with catatonia subsequent to symptoms of depression that remitted with treatment. DAT-SPECT showed a decreased striatal accumulation in all patients, which increased after treatment. Two patients had met the diagnostic criteria of probable dementia with Lewy bodies (DLB), but no longer did so after their symptoms improved. Conclusions: Reversible DAT dysfunction observed in this study suggests that reversible impairment of dopaminergic transmission in the striatum partly underlies catatonia. Careful consideration should be given to diagnosing DLB in patients with decreased DAT-SPECT accumulation, especially when catatonia is present.

DOI： 10.1016/j.jagp.2023.05.009

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Mikiyo Wakamatsu, Masayuki Nakamura, Tsutomu Douchi, Motofumi Kasugai, Shinpei Kodama, Akira Sano, Hiroaki Kobayashi . Predicting postpartum depression by evaluating temperament during pregnancy . Journal of Affective Disorders292 720 - 724 2021.9Reviewed

Language：Japanese Publishing type：Research paper (scientific journal)

Aim: : The purpose of this study was to investigate premorbid temperaments to predict postpartum depression in pregnant women with no previous psychiatric history and to clarify the correlation between postpartum depression and the factors included in the Postpartum Depression Predictors Inventory-Revised (PDPI-R) and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire (TEMPS-A)/Munich Personality Test (MPT). Methods: : A total of 170 eligible pregnant women filled out both questionnaires, the first between the 8th and 23rd week of gestation, and the latter between the 34th and 38th week of gestation. Participants filled out The Edinburgh Postnatal Depression Scale (EPDS) one month postpartum to measure for postpartum depression symptoms. All participants delivered full-term healthy babies. Results: : Seventeen (10%) women met the criteria for postpartum depression with a score of 9 or higher on the EDPS. The factors significantly related to developing postpartum depression were schizoid and melancholic temperament on the TEMPS-A/MPT and marital dissatisfaction on the PDPI-R. The total score on the PDPI-R was significantly correlated with depressive, cyclothymic, irritable, and anxious temperaments on the TEMPS-A/MPT. A lack of social support on the PDPI-R was significantly correlated with depressive, irritable, and anxious temperaments on the TEMPS-A/MPT. Conclusion: : The findings suggest that postpartum depression may be related to schizoid and melancholic temperaments and marital dissatisfaction. The hyperthymic temperament was identified as a significant predictor in preventing PPD. Careful observation during puerperium is recommended if a pregnant woman is likely to have these temperaments or psychological conditions. Temperament evaluation should be done during pregnancy as a form of postpartum depression screening.

DOI： 10.1016/j.jad.2021.05.106

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Yokotsuka-Ishida Saeko, Nakamura Masayuki, Tomiyasu Yoko, Nagai Mio, Kato Yuko, Tomiyasu Akiyuki, Umehara Hiromi, Hayashi Takehiro, Sasaki Natsuki, Ueno Shu-ichi, Sano Akira . Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia(和訳中) . Journal of Human Genetics66 ( 6 ) 597 - 606 2021.6Reviewed

Language：English Publisher：Nature Publishing Group

Marfan症候群様小奇形(MPA)、知的障害および統合失調症(SCZ)を呈した、日本人家系の遺伝子変異について報告した。一塩基多型(SNP)アレイと全エクソームシークエンシングを用いて、ポジショナルクローニングを行った結果、KDM2B遺伝子のPHDドメイン領域エクソン15に、本家系で発症要因と推定されるミスセンス変異(rs1555289644, NM_032590.4: c.2173G>A, p.A725T)が検出された。また、エクソームシークエンシングにより、コード領域内では、KDM2B遺伝子内に検出された唯一の点突然変異が、全ゲノム関連解析から、最も高い対数オッズスコア2.41が示された領域内に存在することが明らかにされた。さらに、ハプロタイプ解析により、罹患家族構成員4例に共分離が認められ、c.2173G>A変異を有する発端者由来リンパ芽球様細胞株でのKDM2B遺伝子発現量は、健常対照者の約半分であることが判明した。以上より、本家系では、発達過程でのKDM2B遺伝子のハプロ不全により、MPA、知的障害およびSCZが発症したと推測された。

Terasaki A, Nakamura M, Urata Y, Hiwatashi H, Yokoyama I, Yasuda T, Onuma T, Wada K, Kaneko S, Kan R, Niwa SI, Hashimoto O, Komure O, Goto YI, Yamagishi Y, Nakano M Furusawa Y, Sano A . DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the non-pathogenic TTTTA repeat expansion in TNRC6A . Journal of Human Genetics 66 ( 4 ) 419 - 429 2021.4Reviewed

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

DOI： 10.1038/s10038-020-00855-0

Umehara Hiromi, Nakamura Masayuki, Nagai Mio, Kato Yuko, Ueno Shu-ichi, Sano Akira . Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation . Journal of Human Genetics66 ( 3 ) 243 - 249 2021.3Reviewed

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

3世代にわたる日本人1家系21例から、健常者10例と統合失調性感情障害1例およびアルコール依存症1例、双極性障害(BD)3例および再発性大うつ病性障害(MDD)3例を対象とし、遺伝的影響が強いと予測される稀少な機能獲得性変異を特定した。100KのSNPアレイとマイクロサテライトマーカーを用いてゲノムワイド連鎖解析を行い、家系内の連鎖領域を指定し、これら連鎖領域内での遺伝子変異を特定するため、BD患者2例の全エキソーム配列決定を行い、DNA変異との共分離を解析した。その結果、最終的にDOCK5遺伝子のエキソン31領域に、機能獲得性変異を示唆する稀少なヘテロ接合変異(c.3170A>G, p.E1057G)が特定された。また、機能ゲノム解析により、DOCK5遺伝子が気分状態や自殺傾向を示すバイオマーカーの1つであることが明らかにされた。DOCK5遺伝子の機能は不明だが、本解析結果から、BDとDOCK5遺伝子との病理学的関係性が指摘された。

DOI： 10.1038/s10038-020-0

中村雅之、佐野輝 . 神経有棘赤血球症 . 生体の科学71 ( 5 ) 392 - 393 2020.10

Kasamo Kei, Nakamura Masayuki, Daimou Yoko, Sano Akira . 複数の遺伝子におけるPRIMPOL変異および変異体は慢性進行性外眼筋麻痺症候群の家族性症例の表現型に関与する(A PRIMPOL mutation and variants in multiple genes may contribute to phenotypes in a familial case with chronic progressive external ophthalmoplegia symptoms) . Neuroscience Research157 58 - 63 2020.8Reviewed

Language：English Publisher：エルゼビア・ジャパン(株)

複数の筋肉ミトコンドリアDNAの欠失、眼瞼下垂、糖尿病、難聴、精神遅滞および情緒不安定を特徴とする慢性進行性外眼筋麻痺症候群様症状を持つ家族について報告した。発端者は69歳男性であった。発達障害と精神遅滞があり、眼瞼下垂や難聴、心室肥厚、運動感覚ニューロパチーがみられた。71歳時に死亡した。家族の核遺伝子変異を特定するために遺伝子解析を行った。その結果、PRIMPOL、BRCA1、CPT2およびGJB2遺伝子における病原性変異の可能性と、CARD8およびMEFV遺伝子における機能的多型が認められた。複数の機能的多型と可能性のある病原性変異は、ミトコンドリア病様表現型に複合的に関与する可能性があると考えられた。

Tada Y, Hamaguchi T, Ikeda Y, Iwasa K, Nishida Y, Nakamura M, Sano A, and Yamada M . Chorea-acanthocytosis with a novel mutation in the vacuolar protein sorting 13 homolog a gene: A case report . J Neurol Sci412 116731 2020.5Reviewed

Futamura A, Nakamura M, Kawamura M, Sano A, and Ono K . Novel VPS13A Gene Mutations in a South Asian, Indian Patient with Chorea‑acanthocytosis. . Neurol India68 ( 206 ) 208 2020.2Reviewed

Urata Y, Nakamura M, Shiokawa N, Yasuniwa A, Takamori N, Imamura K, Hayashi T, Ishizuka T, Sano A . Sleep disorders in four patients with myotonic dystrophy type 1 . Front Neurol11 12 2020.2Reviewed

中島健二、祖父江元、長谷川一子、饗場郁子、青木正志、阿部康二、池内健、小野寺理、梶龍兒、吉良潤一、桑原聡、小久保康昌、斎藤加代子、佐々木秀直、佐野輝、高橋良輔、辻省次、戸田達史、中川正法、野元正弘、服部信孝、村田美穂、村山繁雄、望月秀樹、森田光哉、横田隆徳、吉田眞理、渡辺保裕、保住功（Huntington病の診断、治療、療養の手引きガイドライン作成委員会） . Huntington病の診断、治療、療養の手引き . 神経治療学37 61 - 104 2020.1Invited

Takenobu Murakami, Dan Abe, Hideyuki Matsumoto, Ryo Tokimura, Mitsunari Abe, Amanda Tiksnadi, Shunsuke Kobayashi, Chikako Kaneko, Yuka Urata, Masayuki Nakamura, Akira Sano, Yoshikazu Ugawa . A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs . BMC Neurology19 ( 1 ) 301 2019.11Reviewed

© 2019 The Author(s). Background: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. Case presentation: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. Conclusions: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

DOI： 10.1186/s12883-019-1526-9

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Papers - SANO Akira