Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
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DOI：
10.1038/13810
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发表时间：
1999-10-01
期刊：
影响因子：
30.8
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Amir, RE;Van den Veyver, IB;Zoghbi, HY
Rett综合征(1)(RTT，MIM 312750)是一种进行性神经发育障碍，是女性智力低下的最常见原因之一，发病率为1/10,000-15,000(参考文献)。2)。典型RTT的患者似乎在6-18个月前发育正常，然后逐渐丧失语言和有目的地使用手，并出现小头畸形、癫痫、自闭症、共济失调、间歇性过度换气和刻板印象的手运动(3)。经过最初的消退，病情稳定下来，患者通常能活到成年。由于RTT几乎只发生在女性，有人认为RTT是由X连锁的显性突变引起的，在半合子男性中具有致命性(3-8)。先前使用RTT家系的排除作图研究将该基因定位到Xq28(参考文献6、7、9-11)。利用系统的基因筛查方法，我们已经确定编码X-连锁甲基CpG结合蛋白2(MeCP2)的基因(MECP2)突变是一些RTT的原因。MeCP2选择性地与哺乳动物基因组中的CpG二核苷酸结合，并通过与组蛋白脱乙酰酶和辅阻遏子SIN3A的相互作用来介导转录抑制(参考文献12，13)。在21例散发性白血病患者中，有5例发现了高度保守的甲基结合域(MBD)编码区的3个新发错义突变，以及1个新发移码突变和1个新发无义突变，这两种突变都破坏了转录抑制域(TRD)。在一个RTT家庭的两个受影响的同父异母姐妹中，我们发现了一个额外的错义突变的分离，在她们的专职携带者母亲中没有检测到。这表明母亲是这种突变的生殖系马赛克。我们的研究报告了RTT的第一个致病突变，并指出异常的表观遗传调节是RTT发病的机制。
Rett syndrome(1) (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements(3). After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males(3-8). Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,7,9-11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some Eases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.