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Human Molecular Genetics Advance Access published online on November 3, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi002
© 2004 by Oxford University Press
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Article

Expression of cardiac myosin binding protein C (cMyBP-C) in Drosophila as a model for the study of human cardiomyopathies

Thien Phong Vu Manh 1, Mustapha Mokrane 1, Emmanuelle Georgenthum 1, Jeanne Flavigny 2, Lucie Carrier 3, Michel Sémériva 1, Michel Piovant 1, and Laurence Röder 4*

1 UMR6545 LGPD-IBDM, CNRS-Université de la Méditerranée, Marseille, France
2 INSERM UR582, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
3 INSERM UR582, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Institute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Hamburg, Germany
4 UMR6545 LGPD-IBDM, CNRS-Université de la Méditerranée, Campus de Luminy Case 907, 13288 Marseille Cedex 09, France

* To whom correspondence should be addressed.
Laurence Röder, E-mail: roder{at}ibdm.univ-mrs.fr.


  Abstract

Mutations in the MYBPC3 gene encoding human cardiac myosin binding protein C (cMyBP-C) are associated with familial hypertrophic cardiomyopathy (FHC) but the molecular mechanisms involved are not fully understood. In addition, development of FHC is sensitive to genetic backgrounds and the search for candidate modifier genes is crucial with a view to proposing diagnosis and exploring new therapies. We used Drosophila as a model to investigate the in vivo consequences of human cMyBP-C mutations. We first produced transgenic flies that specifically express human wild type or two C-terminal truncated cMyBP-Cs in the Indirect Flight Muscles (IFM), a tissue particularly amenable to genetic and molecular analyses. Firstly, incorporation of human cMyBP-C in the IFM led to sarcomeric structural abnormalities and a flightless phenotype aggravated by age and gene dosage. Secondly, transcriptome analysis of transgenic IFM using nylon microarrays showed the remodelling of a transcriptional program involving 97 out of 3570 genes. Among them, the Calmodulin gene encoding a key component of muscle contraction found up-regulated in transgenic IFM was evaluated as a potential modifier gene. Calmodulin mutant alleles rescued the flightless phenotype and therefore behave as dominant suppressors of the flightless phenotype suggesting that Calmodulin might be a modifier gene in the context of human FHC. In conclusion, we suggest that the combination of heterologous transgenesis and transcriptome analysis in Drosophila could be of great value as a way to glean insights into the molecular mechanisms underlying FHC and to propose potential candidate modifier genes.


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