Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene

Détails

ID Serval
serval:BIB_731FBFC2010E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene
Périodique
Neurology
Auteur(s)
Haravuori  H., Vihola  A., Straub  V., Auranen  M., Richard  I., Marchand  S., Voit  T., Labeit  S., Somer  H., Peltonen  L., Beckmann  J. S., Udd  B.
ISSN
0028-3878 (Print)
Statut éditorial
Publié
Date de publication
04/2001
Volume
56
Numéro
7
Pages
869-77
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Apr 10
Résumé
BACKGROUND: Tibial muscular dystrophy (TMD), a late-onset dominant distal myopathy, is caused by yet unknown mutations on chromosome 2q, whereas MD with myositis (MDM) is a muscular dystrophy of the mouse, also progressing with age and linked to mouse chromosome 2. For both disorders, linkage studies have implicated titin as a potential candidate gene. METHODS: The authors analyzed major candidate regions in the titin gene by sequencing and Southern blot hybridization, and performed titin immunohistochemistry on TMD patient material to identify the underlying mutation. Western blot studies were performed on the known titin ligands in muscle samples of both disorders and controls, and analysis of apoptosis was also performed. RESULTS: The authors identified almost complete loss of calpain3, a ligand of titin, in the patient with limb-girdle MD (LGMD) with a homozygous state of TMD haplotype when primary calpain3 gene defect was excluded. Apoptotic myonuclei with altered distribution of transcription factor NF-kB and its inhibitor IkBalpha were encountered in muscle samples of patients with either heterozygous or homozygous TMD haplotype. Similar findings were confirmed in the MDM mouse. CONCLUSIONS: These results imply that titin mutations may be responsible for TMD, and that the pathophysiologic pathway following calpain3 deficiency may overlap with LGMD2A. The loss of calpain3 could be a downstream effect of the deficient TMD gene product. The significance of the secondary calpain3 defect for the pathogenesis of TMD was emphasized by similar calpain3 deficiency in the MDM mouse, which is suggested to be a mouse model for TMD. Homozygous mutation at the 2q locus may thus be capable of producing yet another LGMD.
Mots-clé
Animals Calpain/*deficiency Chromosomes, Human, Pair 2/*genetics Haplotypes Humans Immunohistochemistry In Situ Nick-End Labeling *Isoenzymes Linkage (Genetics)/*genetics Mice Muscle Proteins/*genetics Muscles/*pathology Muscular Dystrophies/*genetics/pathology Pedigree Protein Kinases/*genetics
Pubmed
Web of science
Création de la notice
25/01/2008 17:18
Dernière modification de la notice
03/03/2018 18:18
Données d'usage