Moretti Paolo, Zoghbi Huda Y
Baylor College of Medicine, One Baylor Plaza, T807, Mail Stop 225, Houston, TX 77030, USA.
Curr Opin Genet Dev. 2006 Jun;16(3):276-81. doi: 10.1016/j.gde.2006.04.009. Epub 2006 May 2.
Rett syndrome, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), is a leading cause of mental retardation with autistic features in females. MECP2 mutations have also been identified in individuals with a variety of clinical syndromes, including mild learning-disability in females, neonatal encephalopathy in males, and psychiatric disorders, autism and X-linked mental retardation in both males and females. Furthermore, MECP2 duplications have been shown to cause a progressive postnatal neurological disorder. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides flanked by AT-rich segments and recruits a co-repressor complex, thereby altering chromatin structure. Subtle gene expression changes have been identified in Rett patients and mouse models; however, MeCP2 dysfunction has also been shown to cause abnormalities of RNA splicing, suggesting a complex molecular pathogenesis. Discovering which genes are misregulated in the absence of functional MeCP2 and demonstrating their role in causing neuronal dysfunction and disease manifestations are challenging but important steps for understanding the pathogenesis of Rett syndrome and related disorders.
瑞特综合征是一种由编码甲基化CpG结合蛋白2（MeCP2）的X连锁基因突变引起的神经发育障碍，是女性智力发育迟缓并伴有自闭症特征的主要原因。在患有多种临床综合征的个体中也发现了MECP2突变，包括女性的轻度学习障碍、男性的新生儿脑病以及精神疾病、自闭症和男性及女性的X连锁智力发育迟缓。此外，已证明MECP2重复会导致一种进行性产后神经疾病。MeCP2是一种转录抑制因子，它与富含AT的片段侧翼的甲基化CpG二核苷酸结合，并募集共抑制复合物，从而改变染色质结构。在瑞特综合征患者和小鼠模型中已发现了细微的基因表达变化；然而，MeCP2功能障碍也已被证明会导致RNA剪接异常，这表明其分子发病机制很复杂。发现哪些基因在缺乏功能性MeCP2时会发生失调，并证明它们在导致神经元功能障碍和疾病表现中的作用，是理解瑞特综合征及相关疾病发病机制的具有挑战性但又很重要的步骤。
