Phenotyping & genotype-phenotype correlations in NF1

表型分析

• 批准号: 6659049
• 负责人: BRUCE R KORF
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659049
• 关键词: DNA repair; alleles; cell growth regulation; clinical research; fluorescence polarization; gene mutation; genetic markers; genetic polymorphism; genotype; human genetic material tag; human subject; magnetic resonance imaging; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neurofibroma; neurofibromatosis; neurogenetics; nucleic acid repetitive sequence; phenotype; siblings; single nucleotide polymorphism

DESCRIPTION (provided by the applicant): Neurofibromatosis type 1 is an autosomal dominant disorder whose hallmark feature is the occurrence of benign tumors of the nerve sheath, neurofibromas. The disorder is a paradigmatic example of variable expression, including variability both within and between families. Possible contributors include allelic heterogeneity of the NF1 gene mutations, which differ among different affected individuals, modifying genes, and stochastic factors. In this study, we intend to identify genetic modifiers of NF1 using the most readily determined NF1 phenotypes, cutaneous neurofibromas and cafe-au-lait spots, while simultaneously carrying out a detailed quantitative assessment of the variability of NF1 phenotypes and its relationship to NF1 mutation type. We will test whether the nature of the NF1 mutation differs in individuals in the top and bottom 10% for neurofibroma number. We will also use a discordant sib-pair strategy for identification of modifier loci, using polymorphic microsatellite markers to test whether the wild-type NF1 allele acts as a genetic modifier of the effects of its mutant counterpart, and analyzing candidate loci by single nucleotide polymorphism (SNP) analysis. In parallel, we will perform comprehensive quantitative phenotyping of a cohort of independent individuals with NF1. We will gather detailed data concerning numbers of dermal neurofibromas, number of café-au-lait spots, and number and location of internal plexiform neurofibromas and spinal neurofibromas, in addition to any other notable NF1 phenotypes. These data will provide the basis for defining the relationship between different NF1 phenotypes and the contribution of NF1 mutation, NF1 wild-type allele and modifier genes to variation in phenotype. The products of these studies, including clinical data, results of genetic modifier analyses, permanent cell-lines from the NF1 patients, and any available tumor material will be made available to the research community. Elucidation of genetic modifiers, phenotype-phenotype correlations, and genotype-phenotype correlations would all be of clinical importance in NF1, providing the potential to predict individuals at risk of specific complications, or to avoid agents that increase risk of disease progression, and identifying new cellular targets for therapy.

描述（申请人提供）：1型神经纤维瘤病是一种 常染色体显性疾病的标志性特征是良性的出现 神经鞘的肿瘤，神经纤维瘤。该疾病是一种范式 可变表达式的示例，包括内部和之间的可变性 家庭。可能的贡献者包括NF1基因的等位基因异质性 在不同受影响个体之间有所不同的突变修饰基因， 和随机因素。在这项研究中，我们打算确定遗传修饰符 使用最容易确定的NF1表型，皮肤的NF1 神经纤维瘤和Cafe-au-Lait斑点，同时进行 详细的定量评估NF1表型及其变异性及 与NF1突变类型的关系。我们将测试NF1的性质是否 神经纤维瘤的顶部和底部10％的个体突变有所不同 数字。我们还将使用不和谐的同胞策略来识别 修改器基因座，使用多态微卫星标记来测试是否是否 野生型NF1等位基因充当其突变体作用的遗传修饰符 对应物，并通过单核苷酸多态性分析候选基因座 （SNP）分析。同时，我们将执行全面的定量 独立个体与NF1的表型。我们将聚集 有关皮肤神经纤维瘤数量的详细数据，数量 咖啡厅景点以及内丛状的数量和位置 除其他任何显着的NF1外，神经纤维瘤和脊髓神经纤维瘤 表型。这些数据将为定义关系提供基础 在不同的NF1表型和NF1突变的贡献之间 野生型等位基因和改性基因与表型的变异。产品的产品 这些研究，包括临床数据，遗传修饰剂分析的结果，NF1患者的永久性细胞线以及任何可用的肿瘤材料 将提供给研究社区。阐明遗传 修饰符，表型 - 表型相关性和基因型 - 表型 相关性在NF1中都具有临床重要性，提供了 预测有特定并发症风险的人，或者避免 增加疾病进展风险并确定新细胞的药物 治疗的靶标。