Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large family with autosomal dominant inheritance. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The thoc1 knockout (thoc1 mutant) zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the c.547C>G mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

耳蜗毛细胞的凋亡是迈向与年龄相关的听力损失的关键一步。尽管许多基因与迟发性进行性听力损失的遗传原因有关，但很少有基因与促凋亡过程直接相关。通过全基因组连锁分析和全基因组测序，我们确定了杂p.L183V变种THOC1为迟发性，进行性，非综合征型听力在一个大家族的损失与常染色体显性遗传的可能原因。Thoc1是保守的多亚基THO / TREX核糖核蛋白复合物的成员，在小鼠和斑马鱼的毛细胞中高度表达。该THOC1敲除（THOC1由gRNA-Cas9系统产生的斑马鱼突变体）缺乏C-惊吓反应，表明听觉功能障碍。既THOC1突变体和敲低斑马鱼极大地降低毛发细胞数，而后者可通过将人野生型胚胎显微注射获救THOC1的mRNA，但可以显著较小程度由c.547C“G突变体的mRNA。该THOC1不足导致斑马鱼毛细胞凋亡明显。一致地，突变体的转录组测序显示在与p53相关的信号通路中基因表达显着增加。p53的耗竭或使用p53抑制剂Pifithrin-α可显着挽救Thoc1基因敲除斑马鱼的毛细胞丢失。我们的结果表明THOC1缺乏症通过p53介导的毛细胞凋亡导致迟发性进行性听力丧失。据我们所知，这是第一种与THOC1突变有关的人类疾病，可能有助于阐明与年龄有关的听力损失的分子机制。