Mouse screen reveals multiple new genes underlying mouse and human hearing loss

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

成年起病型听力损失是一种极为常见的疾病，但目前学界对其潜在的分子发病机制仍知之甚少，这一短板严重阻碍了相关治疗手段的开发。本研究采用遗传学研究策略，通过一种高灵敏度电生理检测手段——听觉脑干反应（auditory brainstem response, ABR），对大规模新构建的小鼠突变体队列进行筛选，以期鉴定出参与听力损失发生的全新分子。本文将对本次筛选的研究结果进行综述。在我们针对1211个受试基因开展的无偏筛选中，共鉴定出38个与听阈升高相关的未预期关联基因，这提示该类疾病存在极高的遗传异质性。研究还发现了多种不同的听觉病理生理机制，部分突变株系呈现出正常发育后听力反应逐渐衰退的表型，这为揭示参与进行性听力损失的全新分子通路提供了关键线索。其中部分基因与人群中听力阈值的个体差异存在关联，另有一个基因SPNS2与儿童耳聋的发生密切相关。本筛选所发现的维持听力功能所必需的全新通路，为后续开发针对性治疗手段提供了全新的潜在机遇。