Mutations in sarcomere protein genes in left ventricular noncompaction.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Klaassen
Sabine
S
Max Delbrück Center for Molecular Medicine, Robert Roessle Strasse 10, 13092 Berlin, Germany. klaassen@mdc-berlin.de
Probst
Susanne
S
Oechslin
Erwin
E
Gerull
Brenda
B
Krings
Gregor
G
Schuler
Pia
P
Greutmann
Matthias
M
Hürlimann
David
D
Yegitbasi
Mustafa
M
Pons
Lucia
L
Gramlich
Michael
M
Drenckhahn
Jörg-Detlef
JD
Heuser
Arnd
A
Berger
Felix
F
Jenni
Rolf
R
Thierfelder
Ludwig
L
D000199:Actins / Q000235:genetics*; D024722:Cardiac Myosins / Q000235:genetics*; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D006321:Heart / Q000254:growth & development; D006352:Heart Ventricles / Q000002:abnormalities*; D006801:Humans; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D012518:Sarcomeres / Q000737:chemistry / Q000235:genetics*; D020107:Troponin T / Q000235:genetics*
C526913:ACTC1 protein, human; D000199:Actins; C501641:MYH7 protein, human; D020107:Troponin T; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains