Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression.
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.
Daoud
Fatma
F
Institut Cochin, Université Paris Descartes, INSERM, CNRS UMR, France.
Angeard
Nathalie
N
Demerre
Bénédicte
B
Martie
Itxaso
I
Benyaou
Rabah
R
Leturcq
France
F
Cossée
Mireille
M
Deburgrave
Nathalie
N
Saillour
Yoann
Y
Tuffery
Sylvie
S
Urtizberea
Andoni
A
Toutain
Annick
A
Echenne
Bernard
B
Frischman
Martine
M
Mayer
Michèle
M
Desguerre
Isabelle
I
Estournet
Brigitte
B
Réveillère
Christian
C
Penisson-Besnier
Cuisset
Jean Marie
JM
Kaplan
Jean Claude
JC
Héron
Delphine
D
Rivier
François
F
Chelly
Jamel
J
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D003071:Cognition; D015331:Cohort Studies; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D007361:Intelligence Tests; D008297:Male; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000150:complications*; D009154:Mutation; D012720:Severity of Illness Index; D055815:Young Adult
D016189:Dystrophin; C085339:apo-dystrophin 1