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- Title
Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
- Authors
Purevjav, Enkhsaikhan; Arimura, Takuro; Augustin, Sibylle; Huby, Anne-Cecile; Takagi, Ken; Nunoda, Shinichi; Kearney, Debra L; Taylor, Michael D; Terasaki, Fumio; Bos, Johan M; Ommen, Steve R; Shibata, Hiroki; Takahashi, Megumi; Itoh-Satoh, Manatsu; McKenna, William J; Murphy, Ross T; Labeit, Siegfried; Yamanaka, Yoichi; Machida, Noboru; Park, Jeong-Euy; Alexander, Peta M A; Weintraub, Robert G; Kitaura, Yasushi; Ackerman, Michael J; Kimura, Akinori; Towbin, Jeffrey A
- Abstract
Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.
- Publication
Human molecular genetics, 2012, Vol 21, Issue 9, p2039
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/dds022