Résumé :
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Tibial muscular dystrophy (TMD) and limb-girdle muscular dystrophy 2J (LGMD2J) are M-band titinopathies, caused by mutations in the extreme C-terminus of titin. In patients of Finnish descent, TMD/LGMD2J is caused by FINmaj, an indel mutation causing the exchange of four amino acids in the C-terminal domain M10 of titin and predicted to disrupt the Ig fold of the domain. Other known TMD/LGMD2J mutations are missense or nonsense changes affecting M10 or the preceding is7 region. In heterozygotes the FINmaj mutation leads to the mild TMD phenotype, and in homozygotes to the severe LGMD2J. The genotype-phenotype correlations of the other mutations have remained more enigmatic.Loss of C-terminal titin epitopes in LGMD2J suggests that the titinopathy mutations ultimately lead to the proteolytic cleavage or major structural change of M-band titin, presumably disrupting the interactions of titin with its ligands. The protease calpain 3 (CAPN3) binds M-band titin within the region affected by the TMD/LGMD2J mutations. There is CAPN3 deficiency in LGMD2J muscle, and the titinopathies may partly share their molecular pathomechanism with the calpainopathy LGMD2A.In the search of proteins possibly affected in TMD/LGMD2J and LGMD2A, we have identified myospryn (CMYA5, cardiomyopathyassociated 5) as a novel interaction partner of both C-terminal titin and CAPN3. Myospryn is a muscle-specific multifunctional scaffolding protein whose roles remain to be characterized in detail. It has been suggested to function in lysosome biogenesis and positioning through its interaction with BLOC-1 (biogenesis of lysosome-related organelles complex), and in the regulation of protein kinase A (PKA) signalling by binding the PKA RIIalpha regulatory subunit. Myospryn is predominantly localized at the costameres as well as inside the muscle fibres flanking the Z-disc. It has been reported to interact with dystrophin, and mislocalization in the mdx mouse has suggested its involvement in Duchenne muscular dystrophy.To model the pathomechanism of TMD/LGMD2J, we have generated knock-in mice carrying the FINmaj titin mutation in the heterozygous or homozygous state. As the mice seem to reflect well the molecular and pathological aspects of the titinopathies, they can be used for exploring the downstream effects of titin mutations on myospryn and its possible role in the pathogenesis of TMD/LGMD2J. These studies may also shed light on the biological functions of the novel interactions.
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