Genetics of Age-Related Hearing Loss

描述(申请人提供)：老年性听力损失(老年性耳聋)是人类人群中最常见的感觉障碍；大约每3名60岁以上的成年人中就有1人患有严重的听力损失。老年性耳聋的遗传学基础尚不清楚，因为研究这种迟发性复杂的遗传疾病极其困难。实验室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)在近亲交配的小鼠品系中很常见，而且小鼠更容易接受遗传分析。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涉及的病理生理途径也涉及到人类，进一步的小鼠AHL的遗传学研究将大大增加我们对人类老年性耳聋的理解。我们的具体目标是(1)鉴定Chr 10Ahl基因，首先通过等位基因遗传互补测试和基因拯救实验，分析在聋华尔兹鼠中突变的共定位基因CDH23；(2)完善新发现的Chr 5上AHL基因座(Ahl2)的图谱位置，并测试该区域的候选基因；(3)定位其他与AHL有关的基因座，并在统一的菌株背景下分析已定义的基因座组合；以及(4)通过分析患者和匹配对照的连锁不平衡和DNA变化，测试小鼠AHL基因座在人类老年性耳聋中的潜在作用。这项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，有助于人类老年性耳聋的诊断、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.