Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation
Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation
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DOI：
10.1086/426462
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发表时间：
2004-12-01
影响因子：
9.8
通讯作者：
Gécz, J
中科院分区：
文献类型：
--
作者：
Weaving, LS;Christodoulou, J;Gécz, J
Rett综合征(RTT)是一种严重的神经发育障碍，在大多数经典病例中，由X-连锁甲基CpG结合蛋白2基因(MECP2)突变引起。在RTT患者中观察到了很大程度的表型变异，无论是那些带有MECP2突变的患者还是没有MECP2突变的患者。我们描述了一个由一个表型与RTT有相当大重叠的先证者，她的同卵双胞胎妹妹患有自闭症和轻中度智力残疾，以及一个患有严重智力残疾和癫痫的兄弟组成的家庭。在该家系中没有发现致病的MECP2突变，并且包含MECP2基因的Xq28区域在受影响的兄弟姐妹中没有共享。另外三个候选区域包括Xp22.31-PtER的10.3Mb，DXS1135和DXS1214之间的Xp22.12-p22.11，以及DXS1196和DXS1191之间的Xq21.33的16.4Mb。对位于Xp22区的ARX和CDKL5基因进行了测序，发现CDKL5的编码序列(c.183delT)缺失。在对44例RTT病例的筛查中，在一名表型严重重叠的RTT女孩中发现了单个剪接点突变IVS13-1G-->；A。在小鼠大脑中，CDKL5的表达与MeCP2重叠-但不完全相同，其表达不受MeCP2缺失的影响。这些发现证实了CDKL5是与癫痫和X连锁智力低下相关的另一个基因座。这些结果还表明，CDKL5的突变可以导致与RTT重叠的临床表型。然而，CDKL5突变在RTT的特定临床亚组中还是在其他临床表现中更为普遍仍有待确定。
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.