Résumé :
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Communication n° 192 Introduction : Hereditary myopathy with early respiratory failure (HMERF) is a late onset disorder with autosomal dominant inheritance. It was described by Edström and collaborators in 1990 as a distinct, clinical phenotype in seven families originating from different parts of Sweden.The skeletal muscle weakness involved neck flexors, proximal limb muscles and foot extensors. Respiratory failure was a common early symptom and the general cause of the first contact with a physician. There has been no signs of cardiomyopathy. Objective and methods : Two of the families, from the middle part of Sweden, were highly suitable for linkage studies (7) and further on gene identification and these families were selected for genotype-phenotype studies with clinical and moleculare methods. Results : All affected members of the two families had a mutation in the M-band region of the Titin gene (MEX1), which is responsible for calmodulin related phosphorylation and binding of some other components of the sarcomere (1, 2,12). Other families with the same phenotype do not have this MEX-1 Titin mutation. This is the second Titin mutation described, causing skeletal muscle weakness but without cardiac symptoms. The first was reported from Finland, the tibial muscle dystrophy (TMD, Udd's disease). Interestingly, TMD is generated by another M-band Titin mutation (MEX 6), as recently reported by Udd and collaborators . In all our patients with TK mutations and the HMERF phenotype, a segregating Arg>Trp missense mutation was disclosed in the TK regulatory alpha-helix R1, the binding site for e.g. calmodulin. The Arg>Trp mutation results in increased calmodulin affinity for the mutant peptide without causing increased kinase activity. Binding of components in the TK- associated complex to mutant TK was abolished, resulting in aberrant localization of some of these. Conclusions : Thus, altered interactions with signalling molecules around Titin kinase, rather than changes in cytoskeletal function of Titin, may be most relevant for pathogenesis in HMERF!
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