The recently described human
anion channel
Anoctamin (ANO)
protein family comprises at least ten members, many of which have been shown to correspond to
calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder
gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal
limb-girdle muscular dystrophy (
LGMD2L) in three French Canadian families and in a distal non-
dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce
premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The
LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii
atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with
Dysferlin (DYSF) mutations that can cause both
LGMD2B and
Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5
protein is still unknown, its putative
calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in
muscular dystrophies.