Abstract:
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Mutations in the anoctamin 5 (ANO5) gene , which encodes a putative calcium-activated chloride channel, have been described in patients with limb-girdle muscular dystrophy (LGMD2L) and distal myopathies. The mutations described so far are point mutations among which the founder c.191 dup A nul mutation (exon 5) is predominant in Norhern European patients. We report here our findings in a cohort of 41 French patients exhibiting morbid phenotypes compatible with a defect in this gene, ie distal Miyoshi-like myopathy with normal dysferlin, LGMD with quadricipital wasting , asymmetric muscle involvement , highly elevated CK and pseudo metabolic features (myalgia and high CK). A first screening for the common c.191 dup A mutation performed by systematic sequencing of exon 5 showed 5 chromosomes carrying this mutation out of the 82 chromosomes tested, none being homozygous. An extended scanning of the ANO5 study was then performed by sequencing the other exons, on cDNA when a biopsy was available or on DNA, or by quantitative analysis (CGH array). It showed 8 additional point mutations : 2 heterozygous premature nonsense mutations (R50X and Y811X), 6 missense mutations : F579S, L108R, N52K (heterozygous), and R58W (1 homozygous, 1 heterozygous), and one out of frame deletion of exons 15 to 17 (heterozygous) . The new missense mutations are assumed to be pathogenic because there were not found in 126 control subjects, and because they affected conserved residues.The full analysis of the AN05 gene is still in progress. But our preliminary results already indicate that the mutation spectrum in this gene is broader that previously described. We emphasize that the 14 mutated chromosomes carried altogether 8 different mutations of which 6 are novel. Two of the seven patients exhibited a phenotype of exercice intolerance.
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