GENEOTYPE/PHENOTYPE RELATIONSHIPS IN FRAGILE X FAMILIES

脆性X综合征(FXS)是已知的最常见的遗传性疾病 智力低下，但它也可以表现为广泛的 智商正常个体的行为和学习问题 射程。初步研究表明，参与的人数较少。 脆性X嵌合症患者的认知和身体状况(一些 带有预突变的细胞和具有完全突变的其他细胞)或部分 完全突变的甲基化。我们的初步研究显示 FMRI蛋白(FMRP)的表达之间存在显著相关性 和a)在马赛克雄性中具有前突变的细胞的百分比和b) 未甲基化的FMR1基因在男性中的比例 突变。在女性中，具有正常FMR1基因的细胞的百分比 在活跃的X染色体上(激活率)也与 产生FMRP的细胞百分比。该项目将利用一种新的 Ben Oostra博士开发的测量FMRP表达的技术 荷兰除了FMR1 DNA检测(CGG重复数， 甲基化状态和活化率)。这些措施将是 与研究脆性X表型的临床措施相关 在家庭研究形式的背景下的可变性也 解释了背景基因的影响。这项研究结合了 数量化系谱数据的统计建模研究进展 由澳大利亚团队Loesch博士和Huggins博士与 最新的分子和蛋白质研究将在丹佛进行。 150个家庭的900个人将在两个月内接受评估 中心，丹佛和墨尔本，在三年内。评估 包括身体(包括人体测量学和皮纹学研究)， 神经认知(包括执行功能测量)和情绪 对FMR1突变的细微影响敏感的措施。 所有分子和蛋白质研究都将在丹佛由Dr。 安妮特·泰勒。这个项目的特点将是参与是否真正 存在于带有前突变的个体中，并仔细搜索 微妙的嵌合体将在血液和口腔细胞中进行 携带前突变的个体。该项目将成为 其他群体中复杂的基因-表型关系的研究 这些疾病的基因目前正在被定性。

Fragile X syndrome (FXS) is the most common known inherited cause of mental retardation, but it can also manifest as a broad spectrum of behavior and learning problems in individuals with an IQ in the normal range. Preliminary studies have demonstrated less involvement cognitively and physically in fragile X individuals with mosaicism (some cells with a premutation and others with a full mutation) or partial methylation of a full mutation. Our preliminary studies have revealed significant correlations between expression of the FMRI protein (FMRP) and a) the percent of cells with a premutation in mosaic males and b) the percent of cells with an unmethylated FMR1 gene in males with a full mutation. In females, the percent of cells with the normal FMR1 gene on the active X chromosome (activation ratio) also correlates with the percent of cells producing FMRP. This project will utilize a new technique to measure FMRP expression developed by Dr. Ben Oostra in the Netherlands in addition to FMR1 DNA measures (CGG repeat number, methylation status and activation ratio). These measures will be correlated with clinical measures to investigate fragile X phenotypic variability within the context of a family study format that also accounts for the effects of background genes. This study combines the advances in the statistical modeling of quantitative pedigree data developed by the Australian team, Drs. Loesch and Huggins, with the latest molecular and protein studies to be done in Denver. Nine hundred individuals in 150 families will be evaluated at two centers, Denver and Melbourne, over a three-year period. The evaluation includes physical (including anthropometric and dermatoglyphic studies), neurocognitive (including executive function measures) and emotional measures which are sensitive to subtle effects of the FMR1 mutation. All molecular and protein studies will be carried out in Denver by Dr. Annette Taylor. This project will characterize whether involvement truly exists in individuals with the premutation and a careful search for subtle mosaicism will be carried out in blood and buccal cells in individuals with the premutation. This project will be a model for investigation of complex genotype-phenotype relationships in other disorders whose genes are now being characterized.