43rd ANNUAL DROSOPHILA RESEARCH CONFERENCE
April 10-14, 2002

PROGRAM AND ABSTRACT VOLUME
Workshop Abstract

21W
Models of familial hypertrophic cardiomyopathies associated with human cardiac myosin binding protein C and cardiac troponin T mutations. Mustapha Mokrane, Michel Semeriva. Laboratoire de Génétique et Physiologie du Développement, Campus de Luminy Case 907 cedex 09, 13288 Marseille, France.

Mutations in two human sarcomeric proteins, the cardiac Myosin Binding Protein C (cMyBP-C) or the cardiac Troponin T (cTnT) are associated with Familial Hypertrophic Cardiomyopathy (FHC). This genetic disease is generally caused by mutations in the sarcomeric proteins, however the mechanism of the pathology is poorly understood. No homologue of cMyBPC has been found in the Drosophila genome. However, a portion of Projectin, a Drosophila I-band muscle protein involved in stretch activation, shows 30% homology with cMyBPC. We have produced by transgenesis flies that can express wild-type or mutated forms of human cMyBPC and human cTnT under the control of the the UAS. The proteins were correctly expressed and incorporated in the I-bands of the IFM sarcomeres. The global stoichiometry of the major sarcomeric proteins was not affected. Expression of the UAS-myc-cMyBPC in the indirect flight muscle (IFM) using the SG29.1-GAL4 line, resulted in flightless flies with abnormal position of their wings. Electronic Microscopy analysis of the IFM of the flies expressing cMyBPC showed that the muscle fibers had their Z-line/I-band torn. Moreover the sarcomere length was reduced by 10% compared to the wildtype. These results suggest that cMyBPC can interact with yet unidentified sarcomeric proteins to produce hypercontraction of the muscle fibers. Work is in progress to identify the proteins interacting with cMyBPC and characterize genetic networks involved in the flightless phenotype.

Cell Cycle Checkpoints