TY - JOUR
T1 - Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations
AU - Purevjav, Enkhsaikhan
AU - Arimura, Takuro
AU - Augustin, Sibylle
AU - Huby, Anne Cecile
AU - Takagi, Ken
AU - Nunoda, Shinichi
AU - Kearney, Debra L.
AU - Taylor, Michael D.
AU - Terasaki, Fumio
AU - Bos, Johan M.
AU - Ommen, Steve R.
AU - Shibata, Hiroki
AU - Takahashi, Megumi
AU - Itoh-satoh, Manatsu
AU - Mckenna, William J.
AU - Murphy, Ross T.
AU - Labeit, Siegfried
AU - Yamanaka, Yoichi
AU - Machida, Noboru
AU - Park, Jeong Euy
AU - Alexander, Peta M.A.
AU - Weintraub, Robert G.
AU - Kitaura, Yasushi
AU - Ackerman, Michael J.
AU - Kimura, Akinori
AU - Towbin, Jeffrey A.
N1 - Funding Information:
This work was supported in part by a Postdoctoral Fellowship and Beginning-Grant-in-Aid from the American Heart Association (E.P.), the Children’s Cardiomyopathy Foundation (E.P., J.A.T.), the John Patrick Albright Foundation (J.A.T.) and NIH R01 HL53392, The Pediatric Cardiomyopathy Registry and R01 HL087000, The Pediatric Cardiomyopathy Specimen Repository (J.A.T.), Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology and grants from the Ministry of Health, Labour and Welfare, Japan; grants for Japan–France and Japan–Korea collaboration research from the Japan Society for the Promotion of Science; and grants from the Life Science Institute and Association Franc¸aise contre les Myopathies, France (A.K., T.A.); the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (M.J.A.).
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds022
DO - 10.1093/hmg/dds022
M3 - Article
C2 - 22286171
AN - SCOPUS:84859245840
SN - 0964-6906
VL - 21
SP - 2039
EP - 2053
JO - Human molecular genetics
JF - Human molecular genetics
IS - 9
M1 - dds022
ER -