-Sarcoglycan Mutations

Genetic defects of the sarcoglycan (SG) complex (sarcoglycanopathies) are found in patients with autosomal recessive muscular dystrophies (1 –6 ). αSG (50 kDa dystrophin-associated glycoprotein, adhalin) is involved in LGMD2D, mapped on 17q21 (1 – 7 ). The continuing progress in the identification and characterization of new mutations in the -αSG gene increases the need for a method that can rapidly identify point mutations. Among the 10 mutations that have been observed in two or more unrelated families, the R77C mutation is specially frequent (about 40% of patients) (5 9 –12 ). The large geographic distribution of the R77C mutation is explained by a highly mutable CpG mutation hot spot, and not by a founder effect. Because this mutation can be readily and directly detected by a simple polymerase chain reaction (PCR) amplification, followed by enzyme digestion, a prior screening for this mutation could reduce the number of patients to analyze. Besides taking into account the occurrence of frequent mutations, the clinical presentation could also be taken into account in the mutation-detection strategy. The R284C mutation results in a much less severe disease, because some adult patients are ascertained after discovery of high serum creatine kinase (11 ). In R284C homozygotes, αp-SG is moderately decreased in muscle, with little secondary impact on -sarcoglycan. Because an important proportion of patients are compound heterozygotes, the authors chose denaturing gradient gel electrophoresis (DGGE) of PCR products as the method to screen gene regions, in order to find abnormal migration patterns caused by single base changes in DNA sequence.