Human Molecular Genetics Advance Access originally published online on July 14, 2009
Human Molecular Genetics 2009 18(20):3779-3794; doi:10.1093/hmg/ddp320
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Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression
1 Institut Cochin, Université Paris Descartes, INSERM Unité 567, CNRS UMR 81014, Paris, France, 2 Institut de Myologie, Hopital Pitié-Salpétrière, Paris, France, 3 Institut de Psychologie, Université Paris Descartes, Boulogne, France, 4 Institut de Génétique, Montpellier, France, 5 Hôpital de Hendaye, Hendaye, France, 6 Service de Génétique, CHRU de Tours, France, 7 Service de Neuropédiatrie, Hôpital Saint Eloi, Montpellier, France, 8 Association Française Contre les Myopathies, Evry, France, 9 Service de Neuropédiatrie, Hôpital Trousseau, Paris, France, 10 Service de Neuropédiatrie, Hôpital Necker, Paris, France, 11 Service de Neuropédiatrie, Hôpital R Poincaré, Garche, France, 12 Hôpital d'Angers, CHU Angers, France and 13 Service de Neuropédiatrie, Hôpital de Lille, CHR-Lille, France
* To whom correspondence should be addressed at: Institut Cochin, CHU Cochin – 24 Rue du Faubourg Saint Jacques, 75014 Paris, France. Tel: +33 144412410/33 158411227; Fax: +33 144412421/33 158411580; Email: jamel.chelly{at}inserm.fr
Received May 12, 2009; Accepted July 10, 2009
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.