Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, United States of America.
PLoS One. 2010 Jul 7;5(7):e11459. doi: 10.1371/journal.pone.0011459.
Progressive sensorineural hearing loss is the most common form of acquired hearing impairment in the human population. It is also highly prevalent in inbred strains of mice, providing an experimental avenue to systematically map genetic risk factors and to dissect the molecular pathways that orchestrate hearing in peripheral sensory hair cells. Therefore, we ascertained hearing function in the inbred long sleep (ILS) and inbred short sleep (ISS) strains. Using auditory-evoked brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements, we found that ISS mice developed a high-frequency hearing loss at twelve weeks of age that progressed to lower frequencies by 26 weeks of age in the presence of normal endocochlear potentials and unremarkable inner ear histology. ILS mice exhibited milder hearing loss, showing elevated thresholds and reduced DPOAEs at the higher frequencies by 26 weeks of age. To map the genetic variants that underlie this hearing loss we computed ABR thresholds of 63 recombinant inbred stains derived from the ISS and ILS founder strains. A single locus was linked to markers associated with ISS alleles on chromosome 10 with a highly significant logarithm of odds (LOD) score of 15.8. The 2-LOD confidence interval spans approximately 4 Megabases located at position 54-60 Mb. This locus, termed sensorineural hearing loss 1 (Snhl1), accounts for approximately 82% of the phenotypic variation. In summary, this study identifies a novel hearing loss locus on chromosome 10 and attests to the prevalence and genetic heterogeneity of progressive hearing loss in common mouse strains.
进行性感觉神经性听力损失是人类人群中最常见的获得性听力损伤形式。它在近交系小鼠中也非常普遍，为系统地绘制遗传风险因素图谱以及剖析协调周围感觉毛细胞听力的分子途径提供了实验途径。因此，我们确定了近交系长睡眠（ILS）和近交系短睡眠（ISS）品系的听力功能。使用听觉诱发脑干反应（ABR）和失真产物耳声发射（DPOAE）测量，我们发现 ISS 小鼠在 12 周龄时出现高频听力损失，到 26 周龄时听力损失进展到低频，同时内淋巴电位正常，内耳组织学无明显异常。ILS 小鼠表现出较轻的听力损失，在 26 周龄时高频的阈值升高，DPOAE 减少。为了绘制导致这种听力损失的遗传变异，我们计算了 63 个源自 ISS 和 ILS 起始株的重组近交系的 ABR 阈值。一个单一的位点与 10 号染色体上与 ISS 等位基因相关的标记相关联，对数优势（LOD）评分高达 15.8。2-LOD 置信区间跨越约 4 Mb，位于位置 54-60 Mb。这个位点，称为感觉神经性听力损失 1（Snhl1），大约占表型变异的 82%。总之，这项研究确定了 10 号染色体上的一个新的听力损失位点，并证明了常见小鼠品系进行性听力损失的普遍性和遗传异质性。
