Résumé :
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Our study of a large cohort of French-Canadian cases of late-onset recessive limb-girdle muscular dystrophies has demonstrated that there are still a large number of mutated genes to be uncovered that cause LGMD in this population. Some of these families allowed the clinical characterisation of a new form of limb-girdle muscular dystrophy 2L (LGMD2L, MIM 611307) for which we identified the first causal mutations in the Anoctamin 5 (ANO5) gene which lies on chromosome 11p14.3-p15. Mutations in ANO5 also cause a distal myopathy (MMD3, MIM613319). A total of 13 published and unpublished ANO5 mutations were uncovered to date, consisting of seven missense mutations, two nonsense mutations, one splice site mutation, one single base pair duplication, one small insertion/deletion, and one large deletion of exons 15 to 17. We demonstrated that one splice site mutation introduces a premature termination codon and consequently triggered nonsense-mediated mRNA decay (NMD), which supported an underlining ANO5 loss-of-function. The LGMD2L phenotype is characterized by adult-onset proximal weakness with prominent asymmetrical quadriceps femoris and biceps brachii atrophy easily confirmed on MRI, myalgia and high CKs. The MMD3 phenotype is associated with distal weakness in particular of calf muscles. On electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The allelic proximal and distal phenotypes are reminiscent of what is found in dysferlinopathies. Estimated prevalence in Northern England suggests that LGMD2L is twice as common as dysferlinopathy (LGMD2B), making it one of the most common recessive LGMDs. ANO5 was also found to be mutated in a very rare autosomal dominant skeletal syndrome: gnathodiaphyseal dysplasia (GDD, MIM 166260). GDD is characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. ANO5's function is still unknown, but Ano1 and Ano2 function as calcium-activated chloride channel (CaCC). Ano5 is highly expressed in skeletal muscle and is overexpressed in muscles of mdx mice. Our present data favour that ANO5 localizes to intracellular membranes in a striated pattern in close proximity to Z-disk. Surprisingly, despite the predicted loss of ANO5 protein in some patients, with presently available antibodies we have observed on LGMD2L muscle biopsies normal ANO5 striated pattern. The relationship between ANO5's intracellular localization and the documented multifocal sarcolemmal perforations and delay in membrane repair in some MMD3 patients is still undetermined. We will review what is known of the functions of other anoctamins and propose a pathophysiological model for this new myopathic anoctaminopathy.
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