ヌノダ　シンイチ   SHINICHI NUNODA   布田　伸一    所属   医学部 医学科（東京女子医科大学病院）    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.
掲載誌名	正式名：Human mutation 略　 称：Hum Mutat ISSNコード：10597794/10981004
掲載区分	国外
出版社	Wiley Periodicals, Inc.
巻・号・頁	32(12),pp.1481-1491
著者・共著者	Arimura Takuro†, Ishikawa Taisuke, Nunoda Shinichi, Kawai Sachio, Kimura Akinori*
発行年月	2011/12
概要	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
PMID	21898660