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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. METHODS AND 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. CONCLUSION: Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.

Type

Journal article

Journal

Circulation

Publication Date

18/03/2003

Volume

107

Pages

1390 - 1395

Keywords

Actinin, Adolescent, Adult, Aged, Amino Acid Sequence, Cardiomyopathy, Hypertrophic, Family Health, Female, Genetic Predisposition to Disease, Humans, LIM Domain Proteins, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Muscle Proteins, Mutation, Missense, Pedigree, Protein Structure, Tertiary, Sequence Alignment