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

  • Hum Mol Genet. 2012 May 1;21(9):2039-53. doi: 10.1093/hmg/dds022.
Enkhsaikhan Purevjav  1 ,  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 Park ,  Peta M A Alexander ,  Robert G Weintraub ,  Yasushi Kitaura ,  Michael J Ackerman ,  Akinori Kimura ,  Jeffrey A Towbin
Affiliations
  • 1. The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
PMID: 22286171 DOI: 10.1093/hmg/dds022
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.