Titre : | Clinical, molecular and functional study of missense mutations in desmin 2B and non helical tail domains : Communication 444 lors du Congrès international de myologie (International Congress of Myology) 9-13 mai 2005 Nantes, France |
contenu dans : | |
Auteurs : | Vicart P, Auteur ; Goudeau B ; Rodrigues-Lima F ; Fischer D ; Casteras-Simon M ; Fardeau M ; Goldfarb L |
Type de document : | Article |
Année de publication : | 2005 |
Pages : | p 169 |
Langues: | Anglais |
Mots-clés : | colloque ; desmine ; desmine (maladie neuromusculaire liée à) ; génétique moléculaire ; mécanisme d'action ; muscle squelettique ; mutation génétique ; protéine des filaments intermédiaires |
Résumé : |
Communication n° 444. Clinical, molecular and functional study of missense mutations in desmin 2B and tail domains.
Goudeau B.(1); Rodrigues-Lima F(1,2).; Fischer D.(1,3); ,Casteras-Simon M.(1,2); Fardeau M(5). Goldfarb L.(4) and Vicart P.(1,2) (1) FRE CNRS N° 2853, 105, Bd de l'Hôpital, 75013 Paris France. (2) UFR de Biochimie, Université Paris 7, 2, place Jussieu, 75005 Paris, France (3) Dpt of Neurology, Medical Faculty, University of Bonn, Germany; (4) Clinical Neurogenetics Unit, National Institute of Neurological Disorders and Stroke, NIH 5625 Fishers Lane, Bethesda, MD 20892-9404. USA. (5) Institut de Myologie, Hôpital de la Pitié-Salpétrière, Paris, France Desmin-related myopathies (DRM), also called desminopathies, are inherited neuromuscular disorders characterized by adult onset and the delayed accumulation of desmin, a protein belonging to the type III intermediate filament (I.F.) family, and located in the sarcoplasma of skeletal and cardiac muscles. In the highly solicited skeletal muscle, the desmin network participates in maintaining the myofibrils structural integrity. Molecular studies of DRM patients have previously led to the identification of multiple desmin gene mutations. Most of them are clustered at the end of the 2B helical rod domain which is essential for correct network assembly. These mutations were shown to induce desmin positive aggregates in transfected cells. The molecular mechanism implicates disruption of conserved salt bridges or modify a heptad position which are critical structural elements for desmin coil-coil dimerization. Recently, we identified new desmin mutants in the desmin rod domain and in the non helical C-terminal part of the protein. In contrast to most 2B domain mutants, the non helical C-terminal domain mutants lead to less clear cut results. Some of them formed an healthy-looking desmin network in transfected SW13 cells whereas others gave a pathological phenotype. These heterogenous phenotypes may be explained by the fact that the IF non helical tail domain is not essential for IF structure although it may participate in the rate of the IF assembly. In conclusion, the physiopathological process for these non helical C-terminal domain mutants is not clear and probably involves other cellular mechanisms that remains to be elucidated. |