Abstract:
The Anoctamin (ANO) family consists of 10 proteins several of which have been shown to correspond to the elusive calciumactivated chloride channels (CaCCs). CaCCs are gated by increases in intracellular calcium and they have been linked to several cellular functions including epithelial transport, cell volume regulation, olfactory and photoreceptor transduction, cardiac membrane excitability, and smooth muscle contraction. The only reported human mutations linked with the ANO family are dominant mutations in ANO5, which cause a rare bone fragility disorder gnathodiaphyseal dysplasia (GDD1). Recently we have identified recessive ANO5 mutations in patients with proximal limb girdle muscular dystrophy (LGMD2L) and a distal non-dysferlin Miyoshi myopathy (MMD3). The mutations identified consist of splice site, a single adenine duplication and missense. The duplicated adenine is present in LGMD2L and MMD3. The LGMD2L phenotype is characterized by proximal muscle weakness and prominent asymmetric quadriceps atrophy. The MMD3 phenotype is associated with distal weakness in particular of the calf muscles. The clinical heterogeneity associated with ANO5 mutations is reminiscent of that observed with dysferlin mutations which can cause both a LGMD and distal muscular dystrophy. ANO5 mutations are associated with loss of muscle membrane integrity and defective membrane repair. Our studies suggest that ANO5 is a putative calcium-activated chloride channel which may function with dysferlin in membrane repair. Our study has identified a novel group of muscular dystrophies “the Anoctaminopathies”.
