Résumé :
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Tibial muscular dystrophy (TMD) is a dominant late onset distal myopathy caused by mutations in M-line titin. In the few homozygotes known, the same mutations lead to the different, more severe limb-girdle muscular dystrophy LGMD2J. Most of the TMD/LGMD2J mutations, including the Finnish FINmaj, are located in M10, the most C-terminal of titin domains. The molecular pathways behind the titinopathies TMD/LGMD2J are unknown, but muscle selectivity and normal sarcomere ultrastructure suggest a signalling or regulatory defect rather than a structural one. Loss of protein interactions of C-terminal titin is likely, caused by direct disruption of the binding or by cleavage of the entire titin C-terminus. Previously, we have shown a secondary defect of calpain 3, a known ligand of M-line titin, in LGMD2J. Since this is not likely to explain the dominant effect in TMD, we have searched for other interactions of C-terminal titin, possibly disrupted by the mutations in TMD/LGMD2J. In a yeast two-hybrid (Y2H) interaction screen, myospryn (CMYA5, cardiomyopathy-associated 5) was identified as a putative ligand of the titin M10 domain. The interaction seems genuine and specific, as it is disrupted in the Y2H system by the FINmaj mutation. The interaction is also supported by coimmunoprecipitation experiments of transfected proteins. According to Y2H studies, the titin binding involves at least the latter of the two FN3 domains and the following SPRY domain of myospryn C-terminus, but a larger region might participate in the interaction. In vivo studies are in progress to obtain further evidence for the putative interaction and to assess its biological function and possible role in TMD/LGMD2J. Myospryn is a large protein belonging to the TRIM superfamily. It has been suggested to function in lysosome-related organelle biogenesis and positioning as well as in regulating the localized activity of protein kinase A in muscle.
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