Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genet ically heterogeneous group of disorders that affect mainly the proximal mus culature(1). There are eight genetically distinct forms of AR LGMD, LGMD 2A -H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mut ations in the genes encoding calpain 3 (ref. 11) and dysferlin(12). respect ively, and are usually associated with a mild phenotype(11-13). Mutations i n the genes encoding gamma- (ref. 14), alpha- (ref. 5), beta- (refs 6,7) an d delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectiv ely. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex(16,17) (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course(4-8.13- 15.18-20). The LGMD 2C locus maps to a 3-cM interval in 17q11-12 in two Bra zilian families with a relatively mild form of AR LGMD (ref. 9). To positio nally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene enc oding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2C, identify ing a new molecular mechanism for AR LGMD.