MOLECULAR GENETICS OF RETT SYNDROME

RETT 综合征的分子遗传学

• 批准号: 6241057
• 负责人: IGNATIA B VAN DEN VEYVER
• 金额: $ 5.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6241057
• 关键词: Drosophilidae; Rett syndrome; autosome; chromosome translocation; clinical research; family genetics; gene deletion mutation; gene expression; gene mutation; genetic mapping; human genetic material tag; human subject; in situ hybridization; molecular cloning; molecular genetics; molecular pathology; nucleic acid repetitive sequence; nucleic acid sequence; restriction fragment length polymorphism; sex chromosomes

Rett syndrome (RS) is a neurodevelopmental disorder which affects females only and results in severe mental retardation and specific motor and behavioral abnormalities. The majority of RS cases are sporadic, however, familial cases have been documented suggesting that Rett syndrome is a genetic disorder. The familial cases and the exclusive occurrence of the syndrome in females suggest X-linked dominant inheritance with lethality in males, but X-linked or autosomal dominant inheritance with sex-limited expression is also considered. The overall goal of this research proposal is to map and identify the genetic defect in RS. Towards this goal, experiments are designed to investigate the various genetic models for RS. Assuming the X-linkage hypothesis, selected genes within regions concordant in familial RS cases will be evaluated for mutations that lead to loss of function or to inappropriate expression from the inactive X in Rett females. To pursue the identification of the RS mutation irrespective of the model of inheritance or map position, the genomes of RS patients will be compared with those of their parents using representational difference analysis (RDA). Under the hypothesis that sporadic RS cases result from new mutations, RDA is expected to identify de novo mutations/rearrangements. To investigate the hypothesis that RS is an autosomal disorder caused by mutations(s) which have sex-limited penetrance, genetic mapping studies will be carried out in a family with recurrent RS. A genome-wide scan for regions identical-by-descent will identify autosomal candidate regions which may harbor the RS gene. Lastly, to investigate the hypothesis that RS is caused by mutations in a neuronal gene which is sexually-dimorphic, vertebrate homolog(s) of a Drosophila gene expressed exclusively in the brain of female fruitflies (yin) will be identified and characterized. If the vertebrate homolog of yin proves to be sexually-dimorphic in humans, it will be characterized in RS patients by sequence analysis. In summary, a variety of approaches will be pursued to map and identify the RS gene. Identification of the RS gene is crucial for early diagnosis and possibly therapeutic intervention, and for understanding the biology of this developmental disorder.

雷特综合征 (RS) 是一种影响女性的神经发育障碍 只会导致严重的智力障碍和特定的运动和 行为异常。 大多数 RS 病例都是散发性的，但是 家族病例已被记录表明雷特综合征是一种 遗传性疾病。 家族性病例和独家发生 女性综合征提示 X 连锁显性遗传具有致死性 男性，但 X 连锁或常染色体显性遗传，性别受限 表达也被考虑。 本研究计划的总体目标 是绘制和识别 RS 的遗传缺陷。 为了这个目标， 实验旨在研究 RS 的各种遗传模型。 假设 X 连锁假说，区域内选定的基因 将评估家族性 RS 病例中的一致突变是否导致 功能丧失或失活 X 的不适当表达 雷特女性。 追求RS突变的鉴定 无论遗传模型或图谱位置如何，基因组 RS 患者将与其父母的患者进行比较 代表性差异分析（RDA）。 假设 散发性 RS 病例由新突变引起，RDA 有望识别 从头突变/重排。 为了研究 RS 的假设 是一种由具有性别限制的突变引起的常染色体疾病 外显率，遗传图谱研究将在一个家庭中进行 复发性RS。 对血统相同的区域进行全基因组扫描将 识别可能含有 RS 基因的常染色体候选区域。 最后，为了研究 RS 是由基因突变引起的假设 神经元基因，其是两性二态性的，脊椎动物同源物 果蝇基因仅在雌性果蝇大脑中表达 （阴）将被识别和表征。 如果脊椎动物的同系物 阴被证明在人类中具有性别二态性，其特征在于 RS患者的序列分析。 总之，将采取多种方法来绘制和识别 RS基因。 RS基因的鉴定对于早期诊断至关重要 以及可能的治疗干预，以及了解生物学 这种发育障碍。