Genotype-phenotype correlations in 35 Brazilian families with sarcoglycanopathies including the description of three novel mutations.

The limb-girdle muscular dystrophies (LGMDs) are genetically determined progressive disorders clinically defined by the primary involvement of the pelvic and shoulder girdle musculature. Among autosomal recessive LGMDs (LGMD 2), sarcoglycanopathies (LGMD 2C-2F) represent a subgroup caused by mutations in one of the genes that encode γ-, α-, β-, and δ-sarcoglycans (SGs), respectively. The SGs are transmembrane glycoproteins which, together with sarcospan, dystrophin, dystroglycans, syntrophins, and α-dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). In addition to the four SGs that comprise the SG-sarcospan subcomplex of the DGC in striated muscle, a fifth SG, named e-SG, is expressed in a wide variety of tissues. 13 In smooth muscle, e-SG replaces α-SG as an integral component of a unique SG-sarcospan complex composed of e-, β-, γand δ-SGs and sarcospan. Interestingly, it has been shown that mutations in e-SG cause myoclonusdystonia syndrome, an autosomal dominant non-degenerative central nervous system disorder. It is well recognised that the DGC acts as a linker between the cytoskeleton of the muscle cell and the extracellular matrix, providing mechanical support to the plasma membrane during myofibre contraction. 16 17 Besides this structural function, there is now increasing evidence that the DGC might play a role in cellular communication, as highlighted by its interaction with signalling molecules such as calmodulin, nitric oxide synthase, and Grb2. 17 So far, 41, 20, 10, and six distinct pathogenic mutations have been found in the α(LGMD 2D), β(LGMD 2E), γ(LGMD 2C), and δ-SG (LGMD 2F) genes, respectively (Leiden Muscular Dystrophy pages, www.dmd.nl). Severe clinical Duchenne-like presentations tend to be more common among these patients, with onset occurring early in childhood and confinement to a wheelchair before the age of 16; however, milder courses have also been described in LGMD 2C-2E patients who harbour missense mutations. 24–26 Also intriguing is the fact that a few frequent alterations, like c.229C>T (R77C) in the α-SG (LGMD 2D) 27–31 and c.521delT in the γ-SG (LGMD 2C) genes, have been associated with both severe and mild forms. Therefore, the establishment of precise genotype-phenotype correlations has proven a challenge for most researchers working on the sarcoglycanopathies. We have previously reported 23 kindreds affected by one of the sarcoglycanopathies. 22 26 30 32–36 In the present study, we identified another 12 LGMD 2C-2F families among 20 who were screened for the coding region of the α-, β-, γand δ-SG genes. Here we report our main genotype-phenotype correlation findings in these 35 Brazilian families and we discuss possible alternative mechanisms that might be associated with the variability of the clinical course.