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导致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有直接联系。通过全基因组连锁分析和全外显子组测序，我们发现THOC1中的杂合 p.L183V 变异可能是一个常染色体显性遗传大家族中晚发、进行性、非综合征性听力损失的原因。 Thoc1 是保守多亚基 THO/TREX 核糖核蛋白复合物的成员，在小鼠和斑马鱼毛细胞中高度表达。 gRNA-Cas9系统产生的thoc1敲除（ thoc1突变体）斑马鱼缺乏C-惊吓反应，表明听力障碍。 Thoc1突变体和敲低斑马鱼的毛细胞数量都大大减少，而后者可以通过胚胎显微注射人野生型THOC1 mRNA 来挽救，但通过 c.547C>G 突变体 mRNA 的程度要小得多。 Thoc1缺陷导致斑马鱼毛细胞明显凋亡。一致地，突变体的转录组测序显示 p53 相关信号通路中的基因表达显着增加。敲除 p53 或应用 p53 抑制剂 Pifithrin-α 可以显着挽救Thoc1敲低斑马鱼的毛细胞损失。我们的结果表明THOC1缺陷通过 p53 介导的毛细胞凋亡导致迟发性进行性听力损失。据我们所知，这是第一种与THOC1突变相关的人类疾病，可能有助于揭示与年龄相关的听力损失的分子机制。