Human Molecular Genetics Advance Access originally published online on November 3, 2004
Human Molecular Genetics 2005 14(1):7-17; doi:10.1093/hmg/ddi002
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved
Expression of cardiac myosin-binding protein-C (cMyBP-C) in Drosophila as a model for the study of human cardiomyopathies
1CNRS, UMR6545, LGPD-IBDM, Université de la Méditerranée, F-13288, Marseille, France, 2INSERM, U582, Paris, F-75013, France and 3Institute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Hamburg, Germany
* To whom correspondence should be addressed at: LGPD-IBDM, Campus de Luminy Case 907, 13288 Marseille Cedex 09, France. Tel: +33 491269612; Fax: +33 491820682; Email: mailto:roder{at}ibdm.univ-mrs.fr
Received July 20, 2004; Revised September 26, 2004; Accepted October 21, 2004
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 background, and the search for candidate modifier genes is crucial with a view to proposing diagnosis and exploring new therapies. We used Drosophila as the 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 indirect flight muscles (IFM), a tissue particularly amenable to genetic and molecular analyses. First, incorporation of human cMyBP-C into the IFM led to sarcomeric structural abnormalities and to a flightless phenotype aggravated by age and human gene dosage. Second, transcriptome analysis of transgenic IFM using nylon microarrays showed the remodelling of a transcriptional program involving 97 out of 3570 Drosophila 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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