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

• Published in: Human molecular genetics Vol. 21; no. 9; pp. 2039 - 2053
• Main 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.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2012
• Subjects: Animals; Animals, Newborn; Ankyrin; Biological and medical sciences; Cardiology. Vascular system; cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; Cardiomyopathy, Dilated - physiopathology; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - pathology; Cardiomyopathy, Hypertrophic, Familial - physiopathology; Case-Control Studies; Codon, Nonsense; Connexin 43; Desmin; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Genetics of eukaryotes. Biological and molecular evolution; Heart; Humans; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Molecular and cellular biology; Muscle Proteins - chemistry; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle Proteins - physiology; Muscles; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - physiology; Mutation; Mutation, Missense; Myocarditis. Cardiomyopathies; Myocardium; Myocardium - pathology; Myocytes, Cardiac - ultrastructure; Neonates; Nuclear Proteins - metabolism; Nuclear transport; Pedigree; Phenotype; Protein Binding; Protein interaction; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Repressor Proteins - metabolism; Skeletal muscle; Stress; Transgenic mice; vinculin; Heterogeneity; Cardiomyopathy; Heart disease; Cardiovascular disease; Genetics; Mutation; Molecular biology; Hereditary; Myocardial disease
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/dds022

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.