Autosomal Recessive Ala93Thr mutation in caveolin-3 gene : a new family

Caveolin-3 is the muscle-specific protein of the caveolin family. It is expressed both in cardiac and skeletal muscles and it is the principal integral membrane component of caveolae, small vescicular invaginations of the plasma membrane implicated in cell signalling. Mutations in the caveolin-3 gene (CAV3) are associated with four different phenotypes: limb girdle muscular dystrophy 1C (LGMD1C), rippling muscle disease (RMD), distal myopathy and familial iperCKemia. All phenotypes are usually inherited with an autosomal dominant pattern of inheritance. We describe an Italian family which presented an autosomal recessive pattern of inheritance. A 30-year-old man presented with rippling, myotonic discharges at electromyography and elevated serum CK levels. His 34-year-old sister had normal muscular strength but referred rippling after strong exercise. DM1 and DM2 gene analysis was normal. Muscle biopsy was obtained from brachial biceps after written informed consent. Caveolin-3 immunohistochemistry (IHC) analysis and full gene sequencing were ultimately performed. Muscle biopsy showed a mild dystrophic pattern and a partial deficit of caveolin-3 at IHC analysis. Mutation analysis showed the homozygous mutation c.277G>A (Ala93Thr) in the CAV3 gene in both probands. Genetic analysis was extended to parents. They carried the same mutation in heterozygosis, were completely asymptomatic and showed normal cardiac function. The same mutation had been previously described by Kubisch et al. (2005) in homozygosis associated with a severe form of RMD. Our patients did not presented a more severe phenotype that usually seen. We confirmed the presence of intrafamilial variability. So far few missense mutations of the caveolin-3 gene behave as recessive. Genetic confirmation in independent families strengthens the reliability of genetic assessment. The mechanism preserving the integrity of caveolin oligomerisation and sarcolemmal localization in the presence of heterozygous A93T mutant caveolin-3 remains to be understood.