LGMD 2E in Tunisia is caused by a homozygous missense mutation in β-sarcoglycan exon 3

Abstract

Four of the currently recognized autosomal recessive limb-girdle muscular dystrophies (LGMD type 2C–F) are caused by mutations in the genes encoding components of the sarcoglycan complex. LGMD 2C, caused by mutations in γ-sarcoglycan, is prevalent in northern Africa, especially in Tunisia, where this type of muscular dystrophy was originally described. Although the disease initially was assumed to be genetically homogeneous in this region, linkage to the α-sarcoglycan locus (LGMD 2D) has also been found. We have now identified the first Tunisian family with β-sarcoglycanopathy (LGMD 2E), further adding to the genetic heterogeneity of autosomal recessive LGMD in this population. Direct sequencing of the β-sarcoglycan gene revealed a homozygous mutation (G272→T, Arg91Leu) in exon 3. This change affects the same arginine residue in the immediate extracellular domain of the protein that was mutated to a proline (G272→C, Arg91Pro) in a Brazilian family with a severe form of the disease. Immunohistochemical analysis for the sarcoglycan complex demonstrates absence of the known components of the complex in both of these families. We postulate that the immediate extracellular domain of β-sarcoglycan may be important for the assembly and/or maintenance of this complex, potentially mediated by disulfide-bond formation to another sarcoglycan via the single cysteine residue in that domain.