Résumé :
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Recessive mutations in the ANO5 gene cause limb girdle muscular dystrophy type 2L (LGMD2L). Patients with ANO5 mutations present with a pattern of proximal weakness affecting predominantly the pelvic girdle and leg muscles, associated with a less prominent distal leg weakness and high CK values. We have shown that a specific mutation (c.191dupA) in exon 5 is frequent in British and German populations, likely the result of a founder effect of Northern European origin. Indeed, 25% of screened patients harboured the common exon 5 mutation, homozygously in 75% and in compound heterozygosity in the rest. In view of these findings, we aimed to confirm the prevalence of ANO5 gene mutations in different populations and to verify if a population-specific allelic variability was recognizable. We therefore collected an additional cohort of patients with a phenotype suggestive of LGM2L, from different geographic origins (primarily from Germany, France, Spain and USA) and screened for mutations in the ANO5 gene. Pathogenic mutations were identified in 11 (23%) of the 48 screened individuals. The common mutation in exon 5 has been identified in 9 individuals, all in compound heterozygosity with other variants elsewhere in the gene. Two additional patients had compound heterozygous ANO5 mutations not including the common mutation. The newly identified ANO5 mutations were missense changes, splice site mutations or small deletion/duplications and were spread across the gene. No additional mutation hotspots were recognisable, although some variants recurred in more than one individual. These results confirm that mutations in the ANO5 gene represent a cause of LGMD in several European populations of different ethic origin. Differences are recognisable and likely due to different founder effects and recurrent mutations. Although the allelic frequency of the common exon 5 mutation appears lower in non-British LGMD2L patients, screening of exon 5 should still represent an early step in the diagnostic algorithm for LGMD2 patients of European ancestry.
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