MeCP2 mutations in children with and without the phenotype of Rett syndrome
MeCP2 mutations in children with and without the phenotype of Rett syndrome
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DOI：
10.1212/wnl.56.11.1486
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发表时间：
2001-06-12
期刊：
影响因子：
9.9
通讯作者：
Naidu, S
中科院分区：
文献类型：
--
作者：
Hoffbuhr, K;Devaney, JM;Naidu, S
背景：瑞特综合征（RTT）是一种由X连锁的甲基CpG结合蛋白2（MeCP2）基因突变引起的神经发育障碍。
方法：通过变性高效液相色谱（DHPLC）和直接测序对116例经典型和非典型瑞特综合征患者的MeCP2基因突变进行研究。
结果：在63%的患者中鉴定出MeCP2基因的致病性突变，共30种不同突变。在72%的经典型RTT患者和所研究的三分之一非典型病例（25例中的8例）中鉴定出突变。作者发现了17种新突变，包括在一名个体中发现的一种复杂基因重排，涉及两次缺失和一次重复。该重复与3'非翻译区（UTR）内的一个区域相同，这是3' UTR参与RTT的首次报道。作者还报告在两名男性中鉴定出MeCP2突变；一名患有经典RTT的克氏综合征男性（T158M）和一名具有Xq27 - 28倒位和一种新的32bp移码缺失[1154(delS2)]的半合子男性婴儿。对突变类型、X染色体失活状态和临床表现严重程度之间关系的研究发现，不同类型突变之间的临床表现存在显著差异。与靠近MeCP2羧基末端的突变相比，氨基末端的突变与更严重的临床表现显著相关。在两名MeCP2突变的无症状携带者和六名被诊断为非典型或经典RTT的女孩中发现了偏态X染色体失活模式。
结论：该患者系列证实了女性中导致RTT的MeCP2基因突变的高频率，并提供了有关临床变异性（突变类型和位置以及X染色体失活模式）的分子基础的数据。
Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Methods: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Results: Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3 ' untranslated region (UTR), and represents the first report of involvement of the 3 ' UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter's male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(delS2)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. Conclusion: This patient series confirms the high frequency of MeCP2 gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).