Résumé :
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POMT1 and POMT2 are two genes causing alpha-dystroglycanopathies, a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with central nervous system and ocular involvement. We studied the POMT1 and POMT2 genes in genetically undiagnosed CMD and LGMD patients with high CK, with or without mental retardation (MR), selected on features such as hypoglycosylation of alpha-dystroglycan or muscle hypertrophy. We identified POMT1 mutations in 9 patients (4 families) with MR (9), microcephaly (7), cerebellar hypoplasia (3), white matter abnormalities (WMA) (4) and no major ocular involvement. POMT2 mutations were identified in 10 sporadic patients. Two unrelated patients carried the same homozygous p.Tyr666Cys mutation, and 5 had compound heterozygous mutations including the p.Tyr666Cys mutation. By genotyping SNPs and microsatellite markers, we defined a distinct 170 kb-haplotype encompassing POMT2 and shared by all the subjects harboring the p.Tyr666Cys mutation, suggesting that this is an ancestral European mutation. All POMT2 patients with a p.Tyr666Cys mutation presented with very similar phenotype with MR, microcephaly, cerebellar hypoplasia, and no major eye abnormalities. Only one of them had cerebral malformation (temporo-parietal pachygyria). Among the 3 other POMT2 cases, one is a WWS patient who died before the age of 2 and carried a homozygous missense mutation, and two other patients had cerebral malformations (polymicrogyria) without major eye abnormalities. Screening of POMT1 and POMT2 should be considered in patients with CMD associated with MR, microcephaly, cerebellar hypoplasia, WMA or cortical dysplasia, even in the absence of eye involvement. No mutation in these two genes has been identified in patients without MR. Therefore, other genes are better candidates (FKRP, FCMD) in CMD or LGMD patients with alpha-dystroglycan hypoglycosylation and normal intellectual development.
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