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 musculature1. There are eight genetically distinct forms of AR LGMD, LGMD 2A–H (refs 210), 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 dysferlin12, respectively, and are usually associated with a mild phenotype11,12,13. 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 complex16,17 (DGC). Patients with LGMD 2C–F predominantly have a severe clinical course4,5,6,7,8,13,14,15,18,19,20. 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.

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Figure 1: Physical map of the candidate region for the LGMD 2G locus, showing approximate locations of 40 genetic markers.
Figure 2: Haplotype analysis of markers from the 17q11–12 region in LGMD2G families.
Figure 3: DNA sequence electrophoregrams representing the two mutations in the telethonin gene associated with LGMD 2G.
Figure 4: Alignment of the normal (a) and mutated (b) telethonin gene sequences indicates the location of the two-G deletion.
Figure 5: Analysis of the telethonin protein in muscle samples.

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We thank the family members for their constant collaboration; C. Urbani for secretarial assistance; A.A.F.C. Ribeiro, A.L. Sertié, A.M.P. Cerqueira, B. Birren, M. Canovas, W. Caldeira, H. Reimann and E. Stegmann for support and technical assistance; and R.C. Pavanello, I. Pavanello and S.K. Marie for clinical assessment. This research has been supported by grants from the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) and the Programa dos Núcleos de Excelência (PRONEX). D.J. is supported by the Sonderforschungsbereich 469, project A5, of the German Research Council and the European commission (BMH4-98-3865). G.F. and G.V. are supported by the Italian Telethon Foundation, grant 1023 and B41. M.R.P.B. is supported in part by an International Research Scholars grant from the Howard Hughes Medical Institute.

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Correspondence to M. R. Passos-Bueno.

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Moreira, E., Wiltshire, T., Faulkner, G. et al. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 24, 163–166 (2000) doi:10.1038/72822

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