MOLECULAR MECHANISMS LEADING TO RETT SYNDROME

描述：（逐字来自申请人的摘要）Rett综合征（RTT）是一种 儿童早期发病的神经系统疾病，其特征为 发展性退化，丧失语言能力和有目的地使用手， 以及癫痫RTT通常是偶发性的，是一种常见的深刻的原因。 智力迟钝，每10- 15 000名女性中就有1人患有智力迟钝。罕见家族性研究 病例，包括一名严重受影响的男性，提供了压倒性的证据， RTT是由于一个基因的X连锁显性突变的重新发生， 是X染色体失活的产物家族性病例的多态性标记分型 允许排除X染色体的大部分区域， Xq 28上的RTT基因。将确定其他RTT系列， 研究以进一步描绘候选区域。拟议的研究将 使用系统的方法和新技术来识别基因 负责这种疾病，并确定其正常功能， 神经系统;发现突变机制，并确定 突变对神经元发育或存活的影响。的 假设RTT是由于Xq 28中的微缺失，将通过 利用序列标记位点PCR和脉冲场凝胶进行系统缺失搜索 用覆盖Xq 28区域的探针进行电泳分析。的假设 达特a基因组重排导致女性Xq 28中的两个从头突变 与RTT和色素失禁（IP），另一个X连锁显性疾病 在男性中致命，将通过基因组方法和荧光检测， 原位杂交RTT突变导致差异基因的假设 将通过抑制消减杂交方法评估表达 并通过来自含有RTT基因的细胞系的cDNA的比较杂交 并将对照组与基因表达微阵列相匹配。候选基因鉴定 通过上述任何一种方法，映射到Xq 28将被测试突变， 不相关的RTT个体。定位的基因的差异表达模式 基因组中的其他地方可能揭示受RTT影响的途径 基因的功能。此外，人类基因图谱和测序数据库 在候选区域中包含许多基因。其中19人被 优先进行突变分析一旦RTT基因被鉴定出来， 在疾病的早期阶段进行分子诊断将成为可能。 新生儿筛查项目可以识别症状前突变携带者。一 已知致病遗传机制，了解病理生理学 可能导致早期治疗干预。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Rett Syndrome (RTT) is a neurological disorder of early childhood onset that is characterized by developmental regression with loss of speech an of purposeful hand use, microcephaly and seizures. Usually sporadic, RTT is a common cause of profound mental retardation, affecting 1 in 10-15,000 females. Studies of rare familial cases, including a severely affected male, provide overwhelming evidence that RTT is due to de novo occurrence of X-linked dominant mutations of a gene that is subject to X-inactivation. Polymorphic marker typing of familial cases allowed exclusion of most regions of the X chromosome and focused the search for the RTT gene on band Xq28. Additional RTT families will be identified and studied to further delineate the candidate region. The proposed research will use a systematic approach and novel technologies to identify the gene responsible for this disorder and to determine its normal function in the nervous system; to discover the mutational mechanisms and to determine the consequences of the mutations for neuronal development or survival. The hypothesis that RTT is due to microdeletions in Xq28 will be tested by a systematic deletion search using sequence-tagged-sites PCR and pulsed-field-gel electrophoresis analyses with probes covering the Xq28 region. The hypothesis tat a genomic rearrangement causes two de novo mutations in Xq28 in a female with RTT and Incontinentia Pigmenti (IP), another X-linked dominant disorder lethal in males, will be tested by genomic approaches and by fluorescence in situ hybridization. The hypothesis that RTT mutations lead to differential gene expression will be evaluated by suppression subtractive hybridization methods and by comparative hybridization of cDNA from RTT-gene containing cell lines and matched controls to Gene Expression Microarrays. Candidate genes identified by any of the above approaches that map to Xq28 will be tested for mutation in unrelated RTT individuals. Differential expression patterns of genes located elsewhere in the genome may reveal pathways that are influenced by the RTT gene's function. In addition, human gene mapping and sequencing databases contain numerous genes in the candidate region. Nineteen of them have been prioritized for mutation analysis. Once the RTT gene has been identified, Molecular diagnosis will become possible at early stages of the disorder. Newborn screening programs could identify presymptomatic mutation carriers. One the causative genetic mechanism is known, understanding of the pathophysiology may lead to early therapeutic intervention.