MOLECULAR GENETICS OF RETT SYNDROME

Rett综合征（RS）是一种神经退行性疾病， 1/15，000活产女性。 出生时正常，RS患者发展 严重的智力迟钝和运动缺陷。 的 RS的临床过程和病理学提示原发性缺陷中断 中枢神经系统特定亚群的正常发育和维持 神经元 虽然大多数病例是散发性的，但家族性发生表明， X连锁显性遗传和致死性或非致死性的遗传病因学 在男性中表达。 排除作图法使用基因型分析 家族性病例排除了大多数X染色体的RS基因 染色体 鉴定引起RS的基因缺陷是重要的 因为它将允许准确的诊断，并提供关键的洞察力， RS的潜在治疗。 该建议的主要目的是鉴定RS基因 使用四种基本方法来寻找突变。 第一章 代表性差异分析（RDA），一种基于PCR的方法， 分离独特序列将用于检测从头基因 RS患者中的重排。 突变检测的可能性将 通过利用来自多个无关的DNA， 有RS先证者的家庭。 2)RS的可能性来自于 三重重复扩增将使用一组三核苷酸 重复寡聚体用于鉴定含有三联体重复的X连锁基因 序列的 RDA产品和三联体重复序列均将使用 筛选RS患者的DNA突变， 同源cDNA或基因组克隆。 3)X染色体连锁的神经元基因将被 通过Southern和SSC分析筛选突变。 4)候选人X- 将检查连锁基因是否有失活逃逸的证据 通过低甲基化和从失活的S. 将仔细检查确定的潜在RS基因是否存在RS突变 患者的DNA测序，并检查表达内 神经系统发育。 了解基因的正常功能 哺乳动物CNS开发中的产品将阐明 RS表型的发病机制。

Rett Syndrome (RS) is a neurodegenerative disorder which affects up to 1 in 15,000 liveborn females. Normal at birth, RS patients develop profound mental retardation and motor deficits in early childhood. The clinical course and pathology of RS suggest a primary defect interrupting the normal development and maintenance of specific subgroups of CNS neurons. While most cases are sporadic, familial occurrences suggest a genetic etiology with X-linked dominant inheritance and lethality or non- expression in males. Exclusion mapping using genotype analysis of familial cases excluded the putative RS gene from most of the X chromosome. Identification of the gene defect causing RS is important in that it will allow accurate diagnosis and give crucial insight toward potential treatment of RS. The primary aim of this proposal is the identification of the RS gene using four basic approaches to search for the mutation. 1) Representational Difference Analysis (RDA, a PCR-based method for isolation of unique sequences will be used to detect de novo gene rearrangements in RS patients. The likelihood of mutation detection will be maximized through the utilization of DNA from multiple unrelated families with RS probands. 2) The possibility that RS results from a triplet repeat expansion will be explored using a panel of trinucleotide repeat oligomers to identify X-linked genes containing triplet repeat sequences. Both RDA products and triplet repeat sequences will be used to screen DNA from RS patients for mutations as well as to isolate cognate cDNA or genomic clones. 3) X-linked neuronal genes will be screened for mutations by Southern and SSC Analysis. 4) Candidate X- linked genes will be examined for evidence of escape of inactivation manifest by hypomethylation and expression from the inactive S. Potential RS genes identified will be scrutinized for mutations in RS patients by DNA sequencing and examined for expression within the developing nervous system. Understanding the normal function of the gene product in development of the mammalian CNS will elucidate the molecular mechanisms underlying the pathogenesis of the RS phenotype.