Résumé :
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Communication n° 527 Duchenne and Becker muscular dystrophinopathies (DMD and BMD) are allelic X-linked diseases characterized by progressive muscular degeneration, responsible for muscle weakness, and associated with cognitive impairment in approximately one third of the patients. The cognitive impairment is not progressive and its molecular and cellular bases remain poorly understood. In addition to the three promoters giving rise to the three full length isofoms, the dystrophin gene has at least four internal promoters that give rise to shorter dystrophin isoform using a unique fist exon. Abnormalities that affect the distal part of the gene seems to have the major effect on intellectual quotient (IQ) as patients reported so far with mutations affecting the 71 kDa isoform (Dp71) had severe mental retardation. Dp71 is detected in most non muscle tissues including brain, and his promoter and unique first exon are located in intron 62. To reinforce and evaluate the implication of dystrophin products and of the Dp71 isoform in cognitive impairment, a retrospective comparative study have been carried out. On the basis of the molecular study of the dystrophin gene, two groups of patients have been investigated. The first group corresponds to patients with gene mutations located within or beyond exon 62 that will affect the expression of all dystrophin isoforms; the second group corresponds to patients with gene mutations located beyond exon 55, that leave the expression of Dp71 unaffected. In addidtion, we used lymphoblastes / lymphocytes expression of the Dp71 isoform, and whenever possible, transcript and protein isoforms corresponding to Dp71 will also be investigated by quantative RT-PCR, Western Blot and immunocytochemistry. Clinical, neuropsychological and molecular data concerning this large cohort of patients will be discussed. An additional study of the unique first Dp71 exon in a cohort of 406 males with mental retardation (potentially X-linked) have also been performed. Through this study we expect to provide new insights into the contribution of dystrophin products and especially Dp71 isoform in the physiopathology of severe cognitive impairment in DMD/BMD patients.
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