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首页> 美国卫生研究院文献>American Journal of Human Genetics >Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation
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Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

机译：CDKL5突变导致严重的神经发育障碍伴婴儿痉挛和精神发育迟滞

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Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G→A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps—but is not identical to—that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.
机译：Rett综合征（RTT）是一种严重的神经发育障碍，在大多数典型情况下，是由X连锁甲基CpG结合蛋白2基因（MECP2）的突变引起的。在患有RTT的患者中，无论是否患有MECP2突变，都观察到了很大的表型变异。我们描述了一个家庭，一个表型与RTT重叠的先证者，她的自闭症双胞胎姐妹，自闭症和轻度至中度智障，以及一个具有深智障和癫痫发作的兄弟。在该家族中未发现致病性MECP2突变，受影响的兄弟姐妹没有共享包含MECP2基因的Xq28区域。通过微卫星映射确定了其他三个候选区域，包括Xpter和DXS1135之间的Xp22.31-pter处的10.3 Mb，DXS1135和DXS1214之间的Xp22.12-p22.11之间的19.7 Mb，以及DXS1196和DXS1191之间的Xq21.33处的16.4 Mb。 。都位于Xp22区域内的ARX和CDKL5基因在受影响的家族成员中进行了测序，并且在受影响的家族成员的CDKL5中鉴定了编码序列（c.183delT）核苷酸183的缺失。在44例RTT病例的筛查中，在一名具有严重表型重叠RTT的女孩中鉴定出单个剪接位点突变IVS13-1G→A。在小鼠大脑中，Cdkl5的表达与Mecp2的表达重叠（但不相同），并且其表达不受Mecp2丢失的影响。这些发现证实CDKL5是与癫痫和X连锁智力低下有关的另一个基因座。这些结果还表明， CDKL5 中的突变可导致临床表型与RTT重叠。但是， CDKL5 突变是否在RTT的特定临床亚组或其他临床表现中更普遍尚待确定。

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