DEAFNESS IN WS1: SEARCH FOR GENETIC MODIFIERS

WS1 中的耳聋：寻找基因修饰剂

• 批准号: 6526936
• 负责人: ARTI PANDYA
• 金额: $ 8.32万
• 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/6526936
• 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，私家侦探。有浓厚的兴趣 了解遗传性疾病的分子病理学，特别是 小儿 长期目标是在学术领域建立职业生涯 医学，这将使PI研究修改器的重要性， 临床相关遗传疾病中表型变异的基因。 该部目前的项目与这项提议高度相关， 将为PI的职业生涯提供必要的基石 发展听力损失影响至少5%的人口 与出生时或早期严重耳聋的发病率有关 据估计，儿童死亡率约为千分之0.8。 从病因学上讲， 异质性，遗传因素占所有病例的一半 深度耳聋，其中10- 20%是由于特定的 遗传性综合征 Waardenburg综合征（WS）是一种综合征， 包括耳聋，反乌托邦canthorum，白色额发， 异色症 我们参与了2 q35区域的基因定位， WS遗传异质性的发现，以及 PAX 3基因座的突变异质性。 广泛表型 WS 1家族内观察到的变异与 MZ双胞胎表型的一致性强烈表明， 基因对这种变异性有贡献。 本建议， 鉴定和表征个体中导致耳聋的基因 遗传了1型WS基因的人我们已经确定了22个WS 1 至少有2个或更多WS 1兄弟姐妹的家庭都受到影响 耳聋。 这对于通过一个或多个修饰基因进行定位是理想的。 “受影响者”才能接近。 一个两层映射策略， 提出了候选基因搜索之后进行全基因组扫描。 除上述方法外，还将使用非参数分析方法。 传统的参数化方法，以提取最大的信息， 家庭是研究。 我们还将进一步表征光谱 在30个可用的WS 1家族中检测PAX 3突变，并研究其 与修饰基因的潜在相互作用。 成功 鉴定导致WS耳聋的修饰基因可能导致 改进的预测测试。

项目成果

Connexin 26 (GJB2) mutations in the Turkish population: implications for the origin and high frequency of the 35delG mutation in Caucasians.

土耳其人群中的连接蛋白 26 (GJB2) 突变：对白种人中 35delG 突变的起源和高频率的影响。

• DOI: 10.1007/s004390100507
• 发表时间: 2001
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Tekin,M;Akar,N;Cin,S;Blanton,SH;Xia,XJ;Liu,XZ;Nance,WE;Pandya,A
• 通讯作者: Pandya,A

W44C mutation in the connexin 26 gene associated with dominant non-syndromic deafness.

连接蛋白 26 基因中的 W44C 突变与显性非综合征性耳聋相关。

• DOI: 10.1034/j.1399-0004.2001.590409.x
• 发表时间: 2001
• 期刊: Clinical genetics
• 影响因子: 3.5
• 作者: Tekin,M;Arnos,KS;Xia,XJ;Oelrich,MK;Liu,XZ;Nance,WE;Pandya,A
• 通讯作者: Pandya,A

Attitudes of deaf individuals towards genetic testing.

聋人对基因检测的态度。

• DOI: 10.1002/ajmg.a.30051
• 发表时间: 2004
• 期刊: American journal of medical genetics. Part A
• 作者: Taneja,PatriciaRubal;Pandya,Arti;Foley,DebraL;Nicely,LaurenVanner;Arnos,KathleenS
• 通讯作者: Arnos,KathleenS