MOLECULAR GENETICS OF RETT SYNDROME

Rett综合征(RS)是一种影响女性的神经发育障碍 只会导致严重的精神发育迟滞和特殊的运动和 行为异常。然而，大多数RS病例是零星的， 有记录的家族性病例表明Rett综合征是一种 遗传性疾病。家族性病例及其独有发生 女性综合征提示X连锁显性遗传致死性 男性，但X连锁或常染色体显性遗传，性别受限 此外，还考虑了表达式。这项研究提案的总体目标是 是定位和识别RS的遗传缺陷。为了实现这一目标， 实验旨在研究RS的各种遗传模型。 假设X连锁假说，在区域内选择的基因 家族性RS病例的一致性将被评估是否导致突变 由于不活动的X而导致功能丧失或表达不当 雷特雌性。寻求RS基因突变的鉴定 无论遗传模式或图谱位置如何， RS患者将与他们的父母使用 代表性差异分析(RDA)。在这个假设下 散发性RS病例由新突变引起，RDA有望识别 从头开始突变/重排。来调查RS的假说 是一种常染色体疾病，由性别受限的突变(S)引起 外显性，基因图谱研究将在一个具有 复发性RS。对血统相同的区域进行全基因组扫描将 确定可能含有RS基因的常染色体候选区域。 最后，为了调查RS是由一个基因突变引起的假设 神经基因，性别二态，脊椎动物同源物(S) 果蝇基因在雌性果蝇脑中特异表达 (阴)将被识别和表征。如果脊椎动物的同源物 阴在人类中被证明是性二型的，它的特征将是 对RS患者进行序列分析。 总而言之，将采取各种方法来绘制地图和确定 RS基因。RS基因的鉴定是早期诊断的关键 以及可能的治疗干预，以及为了了解生物学 这是一种发育障碍。

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.