title: 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.
abstract: 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.
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. hftse@hkucc.hku.hk
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.forename: Jenny C Y
authors.initials: JC
authors.lastname: Ho
authors.forename: Shing-Wan
authors.initials: SW
authors.lastname: Choi
authors.forename: Yee-Ki
authors.initials: YK
authors.lastname: Lee
authors.forename: Amy W
authors.initials: AW
authors.lastname: Butler
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Ng
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Siu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Wing-Hon
authors.initials: WH
authors.lastname: Lai
authors.forename: Yau-Chi
authors.initials: YC
authors.lastname: Chan
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Zhang
authors.forename: Kenneth W J
authors.initials: KW
authors.lastname: Lay
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.forename: Alan
authors.initials: A
authors.lastname: Colman
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D002454:Cell Differentiation; D003893:Desmin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005091:Exons; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013318:Stroke Volume / Q000235:genetics; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology
chemical_list: D003893:Desmin