Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.
BACKGROUND
Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans.


RESULTS
We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with alpha-actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to alpha-actinin. All 3 index patients were characterized by typical asymmetrical septal hypertrophy. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP.


CONCLUSIONS
Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.
Geier
Christian
C
Universitätsklinikum Charité/Kardiologie am Campus Buch und Virchow Klinikum, Humboldt-Universität zu Berlin, Berlin, Germany.
Perrot
Andreas
A
Ozcelik
Cemil
C
Binner
Priska
P
Counsell
Damian
D
Hoffmann
Katrin
K
Pilz
Bernhard
B
Martiniak
Yvonne
Y
Gehmlich
Katja
K
van der Ven
Peter F M
PF
Fürst
Dieter O
DO
Vornwald
Arnold
A
von Hodenberg
Eberhard
E
Nürnberg
Peter
P
Scheffold
Thomas
T
Dietz
Rainer
R
Osterziel
Karl Josef
KJ
D000185:Actinin / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D060588:LIM Domain Proteins; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3; D000185:Actinin