title: Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: Universitätsklinikum Charité/Kardiologie am Campus Buch und Virchow Klinikum, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Geier
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Cemil
authors.initials: C
authors.lastname: Ozcelik
authors.forename: Priska
authors.initials: P
authors.lastname: Binner
authors.forename: Damian
authors.initials: D
authors.lastname: Counsell
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pilz
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Martiniak
authors.forename: Katja
authors.initials: K
authors.lastname: Gehmlich
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Arnold
authors.initials: A
authors.lastname: Vornwald
authors.forename: Eberhard
authors.initials: E
authors.lastname: von Hodenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheffold
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Karl Josef
authors.initials: KJ
authors.lastname: Osterziel
mesh_terms: 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
chemical_list: D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3; D000185:Actinin