Mutations in the caveolin-3 gene: When are they pathogenic?

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of geneti c disorders usually with autosomal recessive (AR) inheritance and, less oft en, displaying autosomal dominant (AD) inheritance, Mutations in the caveol in-3 gene (CAV-3) associated with a reduction of protein expression cause A D-LGMD1C muscular dystrophy, Based on a previous study in the American and Brazilian population, it has been suggested that CAV-3 mutations might also cause AR-LGMD, Here we report the analysis of the CAV-3 gene in 61 additio nal Brazilian LGMD patients and 100 additional Brazilian normal controls, T wo rare G55S and C71W missense changes previously detected only in LGMD pat ients (and not detected in 100 normal controls from the American population ) were now found in normal Brazilian controls. In addition, we have identif ied a novel R125H missense change in one LGMD female patient that was also found in two of her unaffected siblings. These observations, together with the normal immunofluorescence caveolin pattern in the muscle biopsy from tw o patients with the G55W and R125H changes in the CAV-3 gene suggest that t he G55S, C71W, and R125H polymorphisms, on their own, are not sufficient to produce the pathology, (C) 2001 Wiley-Liss, Inc.