Journal Article

Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression

Fatma Daoud, Nathalie Angeard, Bénédicte Demerre, Itxaso Martie, Rabah Benyaou, France Leturcq, Mireille Cossée, Nathalie Deburgrave, Yoann Saillour, Sylvie Tuffery, Andoni Urtizberea, Annick Toutain, Bernard Echenne, Martine Frischman, Michèle Mayer, Isabelle Desguerre, Brigitte Estournet, Christian Réveillère, Penisson-Besnier, Jean Marie Cuisset, Jean Claude Kaplan, Delphine Héron, François Rivier and Jamel Chelly

in Human Molecular Genetics

Volume 18, issue 20, pages 3779-3794
Published in print October 2009 | ISSN: 0964-6906
Published online July 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp320
Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression

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The presence of variable degrees of cognitive impairment, extending from severe mental retardation to specific deficits, in patients with dystrophinopathies is a well-recognized problem. However, molecular basis underlying mental retardation and its severity remain poorly understood and still a matter of debate. Here, we report one of the largest study based on the comparison of clinical, cognitive, molecular and expression data in a large cohort of 81 patients affected with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products, including Dp71 or all dystrophin products, except Dp71. In addition to the consistent data defining molecular basis underlying mental retardation in DMD, we show that BMD patients with MR have mutations that significantly affect Dp71 expression or with mutations located in exons 75 and 76. We also show that mutations upstream to exon 62, with DMD phenotype, predicted to lead to a loss-of-function of all dystrophin products, except Dp71 isoform, are associated, predominantly, with normal or borderline cognitive performances. Altogether, these reliable phenotype–genotype correlations in combination with Dp71 mRNA and protein expression studies, strongly indicate that loss-of-function of all dystrophin products is systematically associated with severe form of MR, and Dp71 deficit is a factor that contributes in the severity of MR and may account for a shift of 2 SD downward of the intelligence quotient.

Journal Article.  8870 words.  Illustrated.

Subjects: Genetics and Genomics

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