DEAFNESS IN WS1: SEARCH FOR GENETIC MODIFIERS

WS1 中的耳聋：寻找基因修饰剂

• 批准号: 2888710
• 负责人: ARTI PANDYA
• 金额: $ 8.29万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2888710
• 关键词: Waardenburg syndrome; autosomal dominant trait; clinical research; family genetics; gene mutation; genetic disorder; genetic mapping; human genetic material tag; human subject; molecular cloning; sensorineural hearing loss

As a pediatric geneticist, the P.I. has a keen interest in understanding the molecular pathology of inherited disorders, especially in children. The long term goal is to establish a career in academic medicine, which would allow the PI to study the importance of modifier genes for phenotypic variation in clinically relevant genetic disorders. Current Departmental projects are highly relevant to this proposal and will provide the necessary building blocks for the PI's career development. Hearing loss affects at least 5 percent of the population with the incidence of profound deafness at birth or during early childhood being estimated as about 0.8 per 1000. It is etiologically heterogenous, with genetic factors accounting for half of all cases of profound deafness, 10-20 percent of which are due to a specific hereditary syndrome. Waardenburg syndrome (WS) is a symptom complex that includes deafness, dystopia canthorum, white forelock and heterochromia. We participated in mapping the gene to 2q35 region, the discovery of genetic heterogeneity in WS, and in the demonstration of mutational heterogeneity at the PAX3 locus. The extensive phenotypic variation observed within WS1 families combined with the striking concordance for phenotype in MZ twins strongly suggests that modifier gene(s) contribute to this variability. The present proposes to identify and characterize the gene(s) causing deafness in individuals who have inherited a gene for WS type 1. We have identified 22 WS1 families with a minimum of 2 or more WS1 siblings who are both affected with deafness. This is ideal for mapping modifier gene(s) by an "affecteds" only approach. A two tiered mapping strategy involving a candidate gene search followed by a genome wide scan is proposed. Nonparametric methods of analysis will be used in addition to the traditional parametric approach to extract maximum information from families being studies. We will also further characterize the spectrum of PAX3 mutations in 30 available families with WS1 and study their potential interaction with the modifier gene(s). The successful identification of modifier genes which cause deafness in WS could lead to improved predictive testing.

作为一名儿科遗传学家，P.I.有浓厚的兴趣 了解遗传性疾病的分子病理学，尤其是 在儿童中。 长期目标是在学术领域建立职业生涯 医学，这将使 PI 研究修饰符的重要性 临床相关遗传性疾病中表型变异的基因。 当前部门项目与本提案高度相关，并且 将为 PI 的职业生涯提供必要的基础 发展。听力损失影响至少 5% 的人口 出生时或早期严重耳聋的发生率 据估计，儿童期患病率约为每 1000 人 0.8 人。 异质性，遗传因素占所有病例的一半 重度耳聋，其中 10-20% 是由于特定原因造成的 遗传性综合症。 瓦登堡综合征 (WS) 是一种症状复合体 包括耳聋、反乌托邦眼角、白发和 异色症。 我们参与将基因定位到 2q35 区域，即 发现 WS 中的遗传异质性，并证明 PAX3基因座的突变异质性。 广泛的表型 WS1 家族中观察到的变异与惊人的 同卵双胞胎表型的一致性强烈表明修饰符 基因导致了这种变异性。 现建议 识别和表征导致个体耳聋的基因 遗传了 WS 1 型基因的人。我们已鉴定出 22 种 WS1 至少有 2 个或以上 WS1 兄弟姐妹均受到影响的家庭 患有耳聋。 这是通过修饰基因进行映射的理想选择 “受影响”的唯一方法。 两层映射策略涉及 建议搜索候选基因，然后进行全基因组扫描。 除了以下方法之外，还将使用非参数分析方法 传统的参数方法可以从中提取最大信息 家庭正在学习。 我们还将进一步表征频谱 30 个可用的 WS1 家族中的 PAX3 突变并研究它们 与修饰基因的潜在相互作用。 成功者 鉴定引起 WS 耳聋的修饰基因可能会导致 改进预测测试。