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

Background: Tibial muscular dystrophy (TMD), a late-onset dominant distal m yopathy, is caused by yet unknown mutations on chromosome 2q, whereas MD wi th myositis (MDM) is a muscular dystrophy of the mouse, also progressing wi th age and linked to mouse chromosome 2. For both disorders, linkage studie s have implicated titin as a potential candidate gene. Methods: The authors analyzed major candidate regions in the titin gene by sequencing and South ern blot hybridization, and performed titin immunohistochemistry on TMD pat ient material to identify the underlying mutation. Western blot studies wer e performed on the known titin ligands in muscle samples of both disorders and controls, and analysis of apoptosis was also performed. Results: The au thors identified almost complete loss of calpain3, a ligand of titin, in th e patient with limb-girdle MD (LGMD) with a homozygous state of TMD haploty pe when primary calpain3 gene defect was excluded. Apoptotic myonuclei with altered distribution of transcription factor NF-kB and its inhibitor IkB a lpha were encountered in muscle samples of patients with either heterozygou s or homozygous TMD haplotype. Similar findings were confirmed in the MDM m ouse. Conclusions: These results imply that titin mutations may be responsi ble for TMD, and that the pathophysiologic pathway following calpain3 defic iency may overlap with LGMD2A. The loss of calpain3 could be a downstream e ffect of the deficient TMD gene product. The significance of the secondary calpain3 defect for the pathogenesis of TMD was emphasized by similar calpa in3 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.