title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
abstract: OBJECTIVE
  Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized by left ventricular dilatation and impaired systolic contraction. It is a major cause of heart failure and heart transplantation. DCM is of genetic origin in approximately 30% of cases and genetically heterogeneous with the identification of numerous disease genes. However, many new disease genes remain to be discovered. Focusing on gene products located in the sarcomere of cardiomyocytes as disease-causing candidates, we screened the gene encoding the sarcomeric Z-band protein myopalladin (MYPN, OMIM 608517) for mutation.
  
  
  RESULTS
  We sequenced the coding region in 114 (65 familial and 49 sporadic cases) independent DCM patients' DNA and functionally analysed the identified mutations. We identified four independent heterozygous mutations in two families (R1088H and I83fsX105) and two sporadic cases (V1195M, P1112L). For the three missense mutations, the substituted amino acids were conserved among species. All mutations were absent from 400 control subjects. Specific immunolabelling of heart tissue from a proband carrying the R1088H mutation showed a decreased localization of myopalladin at the Z-band area of left ventricular cardiac myofibrils. Analysis of the effects of the mutations after transfection in rat neonate cardiomyocytes indicated sarcomere disorganization and premature cell death associated with the V1195M and P1112L myopalladin expression. Allele-specific expression analysis of mRNA from a patient harbouring the I83fsX105 mutation indicated the absence of the mutated transcript, suggesting a haploinsufficiency mechanism.
  
  
  CONCLUSIONS
  Based on genetic, histological, and functional evidence, we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent.
authors.affiliation: INSERM, U621, Paris F-75013 France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Duboscq-Bidot
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neyroud
authors.forename: Gilles
authors.initials: G
authors.lastname: Dilanian
authors.forename: Alain
authors.initials: A
authors.lastname: Millaire
authors.forename: Valéria
authors.initials: V
authors.lastname: Bors
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis
chemical_list: C426225:MYPN protein, human; D009124:Muscle Proteins; D012333:RNA, Messenger