Molecular and muscle pathology in a series of caveolinopathy patients

Abstract

Mutations in the caveolin‐3 gene (CAV3) cause limb girdle muscular dystrophy (LGMD) type 1C (LGMD1C) and other muscle phenotypes. We screened 663 patients with various phenotypes of unknown etiology, for caveolin‐3 protein deficiency, and we identified eight unreported caveolin‐deficient patients (from seven families) in whom four CAV3 mutations had been detected (two are unreported). Following our wide screening, we estimated that caveolinopathies are 1% of both unclassified LGMD and other phenotypes, and demonstrated that caveolin‐3 protein deficiency is a highly sensitive and specific marker of primary caveolinopathy. This is the largest series of caveolinopathy families in whom the effect of gene mutations has been analyzed for protein level and phenotype. We showed that the same mutation could lead to heterogeneous clinical phenotypes and muscle histopathological changes. To study the role of the Golgi complex in the pathological pathway of misfolded caveolin‐3 oligomers, we performed a histopathological study on muscle biopsies from caveolinopathy patients. We documented normal caveolin‐3 immunolabeling at the plasmalemma in some regenerating fibers showing a proliferation of the Golgi complex. It is likely that caveolin‐3 overexpression occurring in regenerating fibers (compared with caveolin‐deficient adult fibers) may lead to an accumulation of misfolded oligomers in the Golgi and to its consequent proliferation. Hum Mutat 25:82–89, 2005.