Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm015
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mutations in the Z band protein Myopalladin gene and Idiopathic Dilated Cardiomyopathy
1 INSERM, UMR S621, Paris F-75013 France; Université Pierre et Marie Curie-Paris6; IFR14
2 Centre National de Génotypage, Evry, France
3 Département de Génétique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
4 Service de Cardiologie, Lille, France
5 Department of Thoracic and Cardiovascular Surgery, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
6 Département de Cardiologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
7 Centre d'Investigation Biomédicale Pitié-Salpêtrière, AP-HP, Paris, France
8 Centre de Référence maladies cardiaques héréditaires, Paris, France
correspondence to: Dr. Eric Villard, UMR S621, 91 bd de l'Hôpital, 75634 Paris cedex 13, France Tel: 33 1 40 77 96 49; Fax: 33 1 40 77 96 45; E-mail: villard{at}chups.jussieu.fr
Aims: 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 
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
[OMIM]
) for mutation.
Methods: We sequenced the coding region in 114 (65 familial and 49 sporadic cases) independent DCM patients' DNA and functionally analyzed the identified mutations.
Results: We identified 4 independent heterozygous mutations in 2 families (R1088H and I83fsX105) and 2 sporadic cases (V1195M, P1112L). For the 3 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 harboring the I83fsX105 mutation indicated the absence of the mutated transcript, suggesting a haploinsufficiency mechanism.
Conclusion: Based on genetic, histological and functional evidence, we identified a new gene associated with DCM and observed mutations in 3 to 4% of cases in a population of European descent.
Time for primary review: 31 days