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An important step in the diagnostic evaluation of a patient with recessive limb-girdle muscular dystrophy is the immunohistochemical analysis of the components of the sarcoglycan complex in a muscle biopsy specimen. Even though a primary mutation in any of the four sarcoglycan genes (alpha-, beta-,gamma-, delta-sarcoglycan) may cause secondary deficiencies in all the other sarcoglycan proteins, more specific immunohistochemical patterns have emerged with the potential to guide and abbreviate the necessary molecular genetic investigations. In gamma-sarcoglycan mutations, the pattern consists of absent or prominently reduced gamma-sarcoglycan immunoreactivity in combination with reduced but detectable immunoreactivity for the other components, with preservation of delta-sarcoglycan. In five consecutive patients, this pattern was able to predict primary gamma-sarcoglycan mutations. Five different mutations were found, including a recurrent novel splice mutation, a large deletion of the entire gene and a novel missense mutation (Leu90Ser). The mutation Cys283Tyr, previously restricted to Gypsy populations was found in compound heterozygosity with del521T, common in north Africa. The variety of known and novel mutations found indicates that the immunohistochemical profile of gamma-sarcoglycan mutations is not restricted to a particular mutation or type of mutation, but rather is a general reflection of the effect of gamma-sarcoglycan mutations on the composition of the sarcoglycan complex. Complete immunohistochemical analysis with all available sarcoglycan antibodies, therefore, is a useful tool to guide the molecular genetic investigations that are necessary to arrive at the correct genetic diagnosis in a given case.

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.