Elucidation of pathogenesis of muscular dystrophies caused by constitutive extracellular calcium influx

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04846
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Noguchi Satoru 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第一部, 室長 (00370982)
• Co-Investigator(Kenkyū-buntansha): 原 雄二 京都大学, 工学(系)研究科(研究院), 助手 (60362456)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 遺伝性疾患 / ミオパチー / カルシウム / 病態 / モデルマウス

Outline of Final Research Achievements

We identified two dominant mutations in ORAI1 gene in tubular myopathy patients. The patients’ cells and the cells expressing the mutated ORAI1 showed constitutive activation of ORAI1 channels showing extracellular calcium entry dependent on extracellular calcium concentration.
We chronologically analyzed the muscle pathology of mouse model with a dominant ORAI1 mutation. The muscle phenotypes were quite milder, nevertheless they showed necrosis and regeneration.We produced new mouse model with a dominant STIM1 mutation. These mice revealed small body weight and had atrophic muscles. On muscle pathology, severe phenotypes were observed showing remarkable dystrophic changes, necrosis and centrally-placed fibers as well as enhanced fibrosis and ectopic adipose tissue replacement.

Free Research Field

生物化学