Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations

Enkhsaikhan Purevjav, Takuro Arimura, Sibylle Augustin, Anne Cecile Huby, Ken Takagi, Shinichi Nunoda, Debra L. Kearney, Michael D. Taylor, Fumio Terasaki, Johan M. Bos, Steve R. Ommen, Hiroki Shibata, Megumi Takahashi, Manatsu Itoh-satoh, William J. Mckenna, Ross T. Murphy, Siegfried Labeit, Yoichi Yamanaka, Noboru Machida, Jeong Euy ParkPeta M.A. Alexander, Robert G. Weintraub, Yasushi Kitaura, Michael J. Ackerman, Akinori Kimura, Jeffrey A. Towbin

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Article numberdds022
Pages (from-to)2039-2053
Number of pages15
JournalHuman molecular genetics
Issue number9
StatePublished - May 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations'. Together they form a unique fingerprint.

Cite this