Skip Navigation


Cardiovascular Research Advance Access first published online on September 19, 2007
This version [Corrected Proof] published online on October 15, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm015
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
77/1/118    most recent
cvm015v2
cvm015v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Duboscq-Bidot, L.
Right arrow Articles by Villard, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duboscq-Bidot, L.
Right arrow Articles by Villard, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy

Laëtitia Duboscq-Bidot1, Peng Xu2, Philippe Charron1,3,4, Nathalie Neyroud1, Gilles Dilanian1, Alain Millaire5, Valéria Bors6, Michel Komajda1,4,7 and Eric Villard1,8,*

1 INSERM, U621, Paris F-75013 France; Université Pierre et Marie Curie-Paris6, IFR14, UMR-S621, Paris, France
2 Centre National de Génotypage, Evry, France
3 Département de Génétique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
4 Centre de Référence Maladies Cardiaques Héréditaires, Paris, France
5 Service de Cardiologie, Hôpital Cardiologiques, Lille, France
6 Department of Thoracic and Cardiovascular Surgery, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
7 Département de Cardiologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
8 Centre d’Investigation Biomédicale Pitié-Salpêtrière, AP-HP, Paris, France

* Corresponding author. Tel: +33 1 40 77 96 49; fax: +33 1 40 77 96 45. E-mail address: 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 and 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.

Conclusion: 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.

KEYWORDS cardiomyopathy; myopalladin; genetics; cardiomyocyte; mutation

Time for primary review 31 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.