alpha-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations.

alpha-Sarcoglycan (adhalin), a 50-kDa component of the dystrophin-associated complex of proteins, participates in the stabilization of the myofiber plasma membrane in the membrane cytoskeleton. Deficiencies of alpha-sarcoglycan cause a subset of childhood-onset muscular dystrophy (SCARMD) cases. However, secondary deficiencies of alpha-sarcoglycan are common. To begin to establish the rates of false positives (secondary deficiencies), we used immunofluorescence to screen 30 Italian dystrophin-normal muscular dystrophy patient biopsies and identified 4 patients with partial alpha-sarcoglycan deficiency and 2 patients with complete deficiency. The entire alpha-sarcoglycan gene was screened for mutations using RT-PCR and SSCP of messenger RNA isolated from muscle biopsies in each of the six patients. Aberrant SSCP conformers and novel mutations were found only in the two complete immunohistochemical deficient patients. One patient was homozygous for a R34H amino acid substitution, while the other was a compound heterozygote (R77C, D97G). These three missense mutations, with additional mutations we and others have previously described, are all localized in the extracellular domain of alpha-sarcoglycan, and most result in the loss or gain of a positively charged amino acid. These data have strong implications for structure/function maps of the alpha-sarcoglycan molecule. Our results suggest that most patients showing partial alpha-sarcoglycan deficiency exhibit this as a secondary consequence of genetically distinct disorders. In support of this, we show biochemical data indicating that secondary deficiency patients show decreased immunostaining with antibodies directed against alpha-sarcoglycan, while having nearly normal quantities of alpha-sarcoglycan protein on immunoblot. This data also suggests that approximately 5% of childhood-onset dystrophin-normal muscular dystrophy patients will show a primary alpha-sarcoglycan deficiency.