Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression
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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DOI：
10.1093/hmg/ddp320
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发表时间：
2009-10-15
影响因子：
3.5
通讯作者：
Chelly, Jamel
中科院分区：
文献类型：
--
作者：
Daoud, Fatma;Angeard, Nathalie;Chelly, Jamel
肌营养不良症患者存在不同程度的认知障碍，从严重的智力迟钝到特定的缺陷，是一个公认的问题。然而，智力低下的分子基础及其严重程度仍然知之甚少，仍然存在争议。在此，我们报告了一项最大的研究，该研究基于81例Duchenne肌营养不良（DMD）和Becker肌营养不良（BMD）患者的临床、认知、分子和表达数据的比较，这些突变预测影响所有肌营养不良蛋白产物，包括Dp71或所有肌营养不良蛋白产物，除了Dp71。除了一致的数据定义DMD中智力迟钝的分子基础外，我们还发现BMD患者的MR具有显著影响Dp71表达的突变或位于75和76外显子的突变。我们还表明，外显子62上游的DMD表型突变预计会导致除Dp71异构体外的所有肌营养不良蛋白产物的功能丧失，主要与正常或边缘认知表现相关。总之，结合Dp71 mRNA和蛋白表达研究，这些可靠的表型-基因型相关性强烈表明，所有肌营养不良蛋白产物的功能丧失与严重形式的MR有系统关联，Dp71缺陷是导致MR严重程度的一个因素，可能导致智商下降2个标准差。
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.