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*These authors contributed equally to this work.
From the Department of Human Molecular Genetics (Drs. Auranen and Peltonen and H. Haravuori), National Public Health Institute, and Department of Neurology (Dr. Somer), University of Helsinki; Neurological Department (Dr. Udd and A. Vihola), Vaasa Central Hospital, Finland; Department of Pediatrics (Dr. Voit), University of Essen; Faculty for Clinical Medicine (Dr. Labeit), Mannheim, Germany; Généthon (Drs. Richard and Beckman and S. Marchand), Evry, France; Department of Human Genetics (Dr. Peltonen), UCLA School of Medicine, Los Angeles, CA.
Address correspondence and reprint requests to Dr. Bjarne Udd, Department of Neurology, Vaasa Central Hospital, FIN-65130 Vaasa, Finland; e-mail: Bjarne.Udd{at}walli.uwasa.fi
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 IkB
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.
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