de Bruijn Suzanne E, Smits Jeroen J, Liu Chang, Lanting Cornelis P, Beynon Andy J, Blankevoort Joëlle, Oostrik Jaap, Koole Wouter, de Vrieze Erik, Cremers Cor W R J, Cremers Frans P M, Roosing Susanne, Yntema Helger G, Kunst Henricus P M, Zhao Bo, Pennings Ronald J E, Kremer Hannie
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.
J Med Genet. 2020 Jul 6. doi: 10.1136/jmedgenet-2020-106863.
Hearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.
Family and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.
An in-frame deletion of 12 nucleotides in was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0-70 years). A functional effect of the variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.
Collectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy.
听力损失是全球最普遍的残疾之一，对生活质量有重大影响。成人起病型听力损失具有高度遗传性，但遗传原因大多未知，这与儿童起病型听力损失形成对比。
家族和队列研究包括外显子组测序和听力表型特征分析。体外蛋白表达研究了DNA变异的功能效应。
在 中发现一个12个核苷酸的框内缺失，它是成人起病型进行性听力损失的一个高度外显的病因，在来自荷兰的12个家族中作为常染色体显性性状分离。63名与该缺失相关的听力损失受试者表现出不同的听力测定特征，平均（标准差）发病年龄为30.6（14.9）岁（范围0 - 70岁）。与野生型蛋白相比，突变型RIPOR2在耳蜗毛细胞静纤毛中的异常定位以及无法挽救RIPOR2缺陷毛细胞的形态缺陷，证明了该变异的功能效应。令人惊讶的是，在荷兰东南部未因听力损失而入选的22952名个体中，有18名存在该变异。
总体而言，所呈现的数据表明成人起病型听力损失的一种遗传形式相对常见，在荷兰及其他地区可能有成千上万的个体面临风险，这使其成为开发（基因）治疗方法的一个有吸引力的靶点。
