Genetics of Age-Related Hearing Loss

描述（由申请人提供）：与年龄相关的听力损失（老年性耳聋）是人类最常见的感觉缺陷；大约三分之一的60岁以上的成年人患有严重的听力损失。老年性痴呆的遗传基础尚不清楚，因为研究这种晚发性遗传复杂疾病非常困难。实验小鼠为研究人类老年性耳聋提供了有希望的模型，因为年龄相关性听力损失（AHL）在近亲繁殖的小鼠品系中很常见，而且小鼠更容易进行遗传分析。我们已经证明，10号染色体上的一个基因（Ahl）是10多个近交系小鼠Ahl的主要易感因素，a /J小鼠的线粒体突变加剧了这种听力损失。我们假设小鼠的遗传易感性和病理生理途径也涉及人类，并且进一步研究小鼠AHL的遗传将大大增加我们对人类老年性痴呆的理解。我们的具体目标是：(1)鉴定Chr 10 Ahl基因，首先分析Cdh23，这是一种共定位基因，在聋哑华尔兹小鼠中突变，通过等位基因的遗传互补测试和基因拯救实验；(2)对新发现的AHL基因座在Chr 5 （Ahl2）上的定位进行细化，并对该区域的候选基因进行检测；(3)在均匀菌株背景下，绘制更多AHL相关基因座，分析已定义的基因座组合；(4)通过分析患者和匹配对照的连锁不平衡和DNA改变，检测小鼠AHL位点的同源物在人类老年性痴呆中的潜在作用。本研究的长期目标是更好地了解AHL的分子机制和病理生理学，从而有助于人类老年性痴呆的诊断、预防干预和治疗的发展。

DESCRIPTION (provided by applicant): Age-related hearing loss (presbycusis) is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The genetic basis of presbycusis is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (Ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that a mitochondrial mutation in A/J mice exacerbates this hearing loss. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are (1) to identify the Chr 10 Ahl gene, first analyzing Cdh23, a co-localized gene that is mutated in deaf waltzer mice, by genetic complementation tests for allelism and by gene rescue experiments; (2) to refine the map position of a newly discovered AHL locus on Chr 5 (Ahl2) and test candidate genes in the region; (3) to map additional loci that contribute to AHL and analyze defined locus combinations on uniform strain backgrounds; and (4) to test homologs of mouse AHL loci for their potential role in human presbycusis by analyses of linkage disequilibrium and DNA alterations in patients and matched controls. The long-term objectives of this research are to provide a better understanding of the molecular mechanisms and pathophysiology of AHL that could contribute to the development of diagnostics, preventive interventions, and therapies for human presbycusis.