Abstract
Rippling muscle disease is caused by mutations in the gene encoding caveolin-3 (CAV3), the muscle-specific isoform of the scaffolding protein caveolin, a protein involved in the formation of caveolae. In healthy muscle, caveolin-3 is responsible for the formation of caveolae, which are highly organized sarcolemmal clusters influencing early muscle differentiation, signalling and Ca2+ homeostasis. In the present study we examined Ca2+ homeostasis and excitation–contraction (E-C) coupling in cultured myotubes derived from two patients with Rippling muscle disease with severe reduction in caveolin-3 expression; one patient harboured the heterozygous c.84C>A mutation while the other patient harbored a homozygous splice-site mutation (c.102+ 2T>C) affecting the splice donor site of intron 1 of the CAV3 gene. Our results show that cells from control and rippling muscle disease patients had similar resting [Ca2+]i and 4-chloro-m-cresol-induced Ca2+ release but reduced KCl-induced Ca2+ influx. Detailed analysis of the voltage-dependence of Ca2+ transients revealed a significant shift of Ca2+ release activation to higher depolarization levels in CAV3 mutated cells. High resolution immunofluorescence analysis by Total Internal Fluorescence microscopy supports the hypothesis that loss of caveolin-3 leads to microscopic disarrays in the colocalization of the voltage-sensing dihydropyridine receptor and the ryanodine receptor, thereby reducing the efficiency of excitation–contraction coupling. Hum Mutat 32:309–317, 2011. © 2011 Wiley-Liss, Inc.
Highlights
Rippling muscle disease (RMD; MIM# 606072) is a rare autosomal dominant disorder caused by mutations in CAV3 the gene encoding caveolin-3 (CAV3), a caveolin isoform exclusively expressed in skeletal, cardiac and smooth muscles (Betz et al, 2001; Woodman et al, 2004)
Though their exact physiological role is not clear, the above data indicate that caveolin-3 plays an important role in muscle function and mutations in CAV3 have been linked to several hereditary myopathies among which are Limb Girdle Muscular Dystrophy (LGMD; MIM #607801), Rippling Muscle Disease (RMD; MIM #606072), Distal myopathy (DM; MIM# 601253) and HyperCKemia (Woodman et al, 2004; Gazzerro et al, 2010 Betz et al, 2001)
In order to assess this we first monitored whether the absence/reduced levels of CAV3 affects the expression levels of the main components of the excitation-contraction (E-C) coupling machinery, namely the dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR) calcium channels, calsequestrin and the SERCA Ca2+ pump (Treves et al, 2009)
Summary
Rippling muscle disease (RMD; MIM# 606072) is a rare autosomal dominant disorder caused by mutations in CAV3 (access # 601253) the gene encoding caveolin-3 (CAV3), a caveolin isoform exclusively expressed in skeletal, cardiac and smooth muscles (Betz et al, 2001; Woodman et al, 2004). Experiments on zebrafish have demonstrated that injection of embryos with CAV3 antisense morpholinos results in embryos with uncoordinated movements probably due to disorganized fused myoblasts, chaotic filament bundles of the contractile proteins, dispersed mitochondria and poorly developed T-tubules (Nixon et al, 2005) Though their exact physiological role is not clear, the above data indicate that caveolin-3 plays an important role in muscle function and mutations in CAV3 have been linked to several hereditary myopathies among which are Limb Girdle Muscular Dystrophy (LGMD; MIM #607801), Rippling Muscle Disease (RMD; MIM #606072), Distal myopathy (DM; MIM# 601253) and HyperCKemia (Woodman et al, 2004; Gazzerro et al, 2010 Betz et al, 2001). Clinical evidences have demonstrated that the same CAV3 mutation in different populations and even within the same family, can result in a different clinical phenotype, indicating the influence of additional factor(s) in the phenotypic outcome of the mutation
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