A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy
A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy
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DOI：
10.1038/ejhg.2013.169
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发表时间：
2014-04-01
影响因子：
5.2
通讯作者：
Kleefstra, Tjitske
中科院分区：
文献类型：
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作者：
de Brouwer, Arjan P. M.;Nabuurs, Sander B.;Kleefstra, Tjitske
通过对86个已知的X连锁智力残疾（ID）基因的外显子进行测序，我们在一个具有非特异性X连锁智力残疾（ID）的家族中发现了肌营养不良蛋白基因（DMD）c.9711_9713del中3个碱基对的缺失。这种框内缺失导致抗肌萎缩蛋白脑特异性同种型Dp 71中单个氨基酸残基Leu 3238的缺失。连锁分析支持因果关系，因为突变存在于Xp22.11-Xp21.1的7.6 cM连锁区间内，最大阳性LOD评分为2.41（MRX 85基因座）。分子模型预测，P。（Leu 3238 del）缺失导致肌营养不良蛋白的C-末端结构域的不稳定，并因此降低与β-肌营养不良蛋白聚糖相互作用的能力。相应地，索引患者的淋巴母细胞样细胞中的Dp 71蛋白水平比对照细胞系中的低6.7倍（P = 0.08）。随后测定指示患者血液中的肌酸激酶水平显示血清肌酸激酶轻度但显著升高，这与肌营养不良蛋白功能受损一致。总之，我们已经确定了Dp 71中的第一个DMD突变，该突变导致ID而没有肌营养不良症。
We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with beta-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P = 0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.