TY - JOUR
T1 - Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy
AU - Arimura, Takuro
AU - Bos, J. Martijn
AU - Sato, Akinori
AU - Kubo, Toru
AU - Okamoto, Hiroshi
AU - Nishi, Hirofumi
AU - Harada, Haruhito
AU - Koga, Yoshinori
AU - Moulik, Mousumi
AU - Doi, Yoshinori L.
AU - Towbin, Jeffrey A.
AU - Ackerman, Michael J.
AU - Kimura, Akinori
N1 - Funding Information:
This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by a research grant from the Ministry of Health, Labour and Welfare, Japan, and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation; by research grants from the Japan Heart Foundation and the Association Française contre les Myopathies (Grant No. 11737; Drs. Arimura and Kimura); and by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (Dr. Ackerman). Dr. Moulik is supported by a Career Development grant from the National Institutes of Health (K08HL091176). Drs. Arimura and Bos contributed equally to this work.
PY - 2009/7/21
Y1 - 2009/7/21
N2 - Objectives: The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. Background: Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin. Methods: We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes. Results: Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes. Conclusions: CARP abnormalities may be involved in the pathogenesis of HCM.
AB - Objectives: The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. Background: Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin. Methods: We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes. Results: Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes. Conclusions: CARP abnormalities may be involved in the pathogenesis of HCM.
KW - Z-disc
KW - cardiac ankyrin repeat protein
KW - hypertrophic cardiomyopathy
KW - mutation
KW - titin/connectin
UR - http://www.scopus.com/inward/record.url?scp=67650091283&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650091283&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2008.12.082
DO - 10.1016/j.jacc.2008.12.082
M3 - Article
C2 - 19608031
AN - SCOPUS:67650091283
SN - 0735-1097
VL - 54
SP - 334
EP - 342
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 4
ER -