Patient-specific induced-pluripotent stem cells-derived cardiomyocytes recapitulate the pathogenic phenotypes of dilated cardiomyopathy due to a novel DES mutation identified by whole exome sequencing

被引:80
作者
Tse, Hung-Fat [1 ,2 ,11 ,12 ]
Ho, Jenny C. Y. [1 ,2 ]
Choi, Shing-Wan [3 ]
Lee, Yee-Ki [1 ]
Butler, Amy W. [3 ,7 ]
Ng, Kwong-Man [1 ]
Siu, Chung-Wah [1 ,2 ]
Simpson, Michael A. [8 ]
Lai, Wing-Hon [1 ]
Chan, Yau-Chi [1 ]
Au, Ka-Wing [1 ]
Zhang, Jinqiu [9 ]
Lay, Kenneth W. J. [9 ]
Esteban, Miguel A. [10 ,11 ,12 ]
Nicholls, John M. [4 ]
Colman, Alan [9 ]
Sham, Pak C. [3 ,5 ,6 ]
机构
[1] Univ Hong Kong, Queen Mary Hosp, Dept Med, Div Cardiol, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Res Ctr Heart Brain Hormone & Hlth Aging, Hong Kong, Hong Kong, Peoples R China
[3] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China
[4] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[5] Univ Hong Kong, Ctr Genom Sci, Hong Kong, Hong Kong, Peoples R China
[6] Univ Hong Kong, Li Ka Shing Fac Med, State Key Lab Cognit & Brain Sci, Hong Kong, Hong Kong, Peoples R China
[7] Kings Coll London, Inst Psychiat, MRC Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England
[8] Kings Coll London, Sch Med, Guys Hosp, Div Genet & Mol Med, London WC2R 2LS, England
[9] ASTAR, Inst Med Biol, Stem Cell Dis Models, Singapore, Singapore
[10] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Key Lab Regenerat Biol, Guangzhou, Guangdong, Peoples R China
[11] Univ Hong Kong, Hong Kong Guangdong Joint Lab Stem Cell & Regener, Hong Kong, Hong Kong, Peoples R China
[12] Guangzhou Inst Biomed & Hlth, Guangzhou, Peoples R China
关键词
SKELETAL; GENERATION; MYOPATHY;
D O I
10.1093/hmg/dds556
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In this paper, we report a novel heterozygous mutation of A285V codon conversion on exon 4 of the desmin (DES), using whole exome sequencing (WES) in an isolated proband with documented dilated cardiomyopathy (DCM). This mutation is predicted to cause three-dimensional structure changes of DES. Immunohistological and electron microscopy studies demonstrated diffuse abnormal DES aggregations in DCM-induced-pluripotent stem cell (iPSC)-derived cardiomyocytes, and control-iPSC-derived cardiomyocytes transduced with A285V-DES. DCM-iPSC-derived cardiomyocytes also exhibited functional abnormalities in vitro. This is the first demonstration that patient-specific iPSC-derived cardiomyocytes can be used to provide histological and functional confirmation of a suspected genetic basis for DCM identified by WES.
引用
收藏
页码:1395 / 1403
页数:9
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