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 genetically heterogeneous group of disorders that affect mainly the proximal musculature 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 mutations in the genes encoding calpain 3 (ref. 11 ) and dysferlin 12 , respectively, and are usually associated with a mild phenotype 11 , 12 , 13 . Mutations in the genes encoding γ-(ref. 14 ), α-(ref. 5 ), β-(refs 6 , 7 ) and δ (ref. 15 )-sarcoglycans are responsible for LGMD 2C to 2F, respectively. 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 , 5 , 6 , 7 , 8 , 13 , 14 , 15 , 18 , 19 , 20 . The LGMD 2G locus maps to a 3-cM interval in 17q11–12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9 ). To positionally 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 encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.