Tübingen Hearing Research Centre, Department of Otolaryngology, Head & Neck Surgery, University of Tübingen Medical Center, 72076 Tübingen, Germany.
Genes (Basel). 2020 Nov 26;11(12):1411. doi: 10.3390/genes11121411.
The gene encodes otoferlin, a critical protein at the synapse of auditory sensory cells, the inner hair cells (IHCs). In the absence of otoferlin, signal transmission of IHCs fails due to impaired release of synaptic vesicles at the IHC synapse. Biallelic pathogenic and likely pathogenic variants in predominantly cause autosomal recessive profound prelingual deafness, DFNB9. Due to the isolated defect of synaptic transmission and initially preserved otoacoustic emissions (OAEs), the clinical characteristics have been termed "auditory synaptopathy". We review the broad phenotypic spectrum reported in patients with variants in that includes milder hearing loss, as well as progressive and temperature-sensitive hearing loss. We highlight several challenges that must be addressed for rapid clinical and genetic diagnosis. Importantly, we call for changes in newborn hearing screening protocols, since OAE tests fail to diagnose deafness in this case. Continued research appears to be needed to complete otoferlin isoform expression characterization to enhance genetic diagnostics. This timely review is meant to sensitize the field to clinical characteristics of DFNB9 and current limitations in preparation for clinical trials for gene therapies that are projected to start in 2021.
该基因编码耳声发射蛋白（otoferlin），它是听觉感觉细胞（内毛细胞）突触的关键蛋白。如果没有 otoferlin，由于内毛细胞突触中突触小泡释放受损，信号传递就会失败。主要位于 上的双等位致病性和可能致病性变体导致常染色体隐性遗传性重度语前聋（DFNB9）。由于突触传递的孤立缺陷和最初保留的耳声发射（OAE），临床特征被称为“听觉突触病”。我们回顾了在 变体患者中报告的广泛表型谱，包括更轻的听力损失以及进行性和温度敏感的听力损失。我们强调了必须解决的几个挑战，以便快速进行临床和遗传诊断。重要的是，我们呼吁改变新生儿听力筛查方案，因为在这种情况下，OAE 测试无法诊断耳聋。似乎需要进一步研究以完成 otoferlin 同工型表达特征的描述，从而增强遗传诊断。本次及时的综述旨在使该领域了解 DFNB9 的临床特征，并为预计将于 2021 年开始的 otoferlin 基因治疗临床试验做好准备。
