Cardiac Ankyrin Repeat Protein Gene ( ANKRD1 ) Mutations in Hypertrophic Cardiomyopathy

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-causin...

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Bibliographic Details
Published in:Journal of the American College of Cardiology 2009-07, Vol.54 (4), p.334-342
Main Authors: Arimura, Takuro, DVM, PhD, Bos, J. Martijn, MD, Sato, Akinori, MD, Kubo, Toru, MD, PhD, Okamoto, Hiroshi, MD, PhD, Nishi, Hirofumi, MD, PhD, Harada, Haruhito, MD, PhD, Koga, Yoshinori, MD, PhD, Moulik, Mousumi, MD, Doi, Yoshinori L., MD, PhD, Towbin, Jeffrey A., MD, Ackerman, Michael J., MD, PhD, Kimura, Akinori, MD, PhD
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Biological and medical sciences
cardiac ankyrin repeat protein
Cardiology
Cardiology. Vascular system
Cardiomyocytes
Cardiomyopathy
Cardiomyopathy, Hypertrophic - genetics
Cardiovascular
Cardiovascular disease
Cloning
Deoxyribonucleic acid
DNA
Family medical history
Female
Gene expression
Genetic Predisposition to Disease
Heart
Heart attacks
Humans
hypertrophic cardiomyopathy
Internal Medicine
Male
Medical sciences
Middle Aged
Muscle Proteins - genetics
Mutagenesis
Mutation
Mutation, Missense
Myocarditis. Cardiomyopathies
Nuclear Proteins - genetics
Pathogenesis
Proteins
Rats
Repressor Proteins - genetics
Studies
titin/connectin
Z-disc
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Summary: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.
ISSN:0735-1097
1558-3597
DOI:10.1016/j.jacc.2008.12.082