Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in...

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Published in:Circulation (New York, N.Y.) N.Y.), 2008-06, Vol.117 (22), p.2893-2901
Main Authors: KLAASSEN, Sabine, PROBST, Susanne, GRAMLICH, Michael, DRENCKHAHN, Jörg-Detlef, HEUSER, Amd, BERGER, Felix, JENNI, Rolf, THIERFELDER, Ludwig, OECHSLIN, Erwin, GERULL, Brenda, KRINGS, Gregor, SCHULER, Pia, GREUTMANN, Matthias, HURLIMANN, David, YEGITBASI, Mustafa, PONS, Lucia
Format: Article
Language:English
Subjects:
Actins - genetics
Associated diseases and complications
Biological and medical sciences
Blood and lymphatic vessels
Cardiac Myosins - genetics
Cardiology. Vascular system
Cardiomyopathies - etiology
Cardiomyopathies - genetics
Cohort Studies
Diabetes. Impaired glucose tolerance
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
DNA Mutational Analysis
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Heart - growth & development
Heart Ventricles - abnormalities
Humans
Medical sciences
Mutation
Myosin Heavy Chains - genetics
Sarcomeres - chemistry
Sarcomeres - genetics
Troponin T - genetics
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Summary:Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.
ISSN:0009-7322
1524-4539
DOI:10.1161/circulationaha.107.746164