THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis

Abstract

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.

Involvement of the SIRT1/PGC-1α Signaling Pathway in Noise-Induced Hidden Hearing Loss

“…It’s reported that in comparison with the normal group, the NIHL group had significantly increased mRNA and protein expression of p53 ( Zhang et al, 2020a ). p53 also affected the pathological process of age-related hearing loss ( Zhang et al, 2020b ) and drug-induced hearing loss ( Ding et al, 2012 ). SIRT1 is reported to increase the expression of MnSOD by deacetylating p53, thus enhancing cellular antioxidant capacity ( Iside et al, 2020 ).…”

Genome-Wide Association Studies Reveal Neurological Genes for Dog Herding, Predation, Temperament, and Trainability Traits

“…It is noted that THOC1 gene is involved in presynaptic development and plays roles in dopamine neuron survival ( 43 ). It is also one causative gene for human late-onset hearing loss ( 64 ). Herding dogs have been selectively bred to detect and react to slight differences in whistle commands from a long distance of nearly 1 km, and excellent hearing ability is necessary for herding tasks ( 65 ).…”

Multiplexed Genome Editing for Efficient Phenotypic Screening in Zebrafish

“…Its genome shares over 80% similarity with humans, and the structure and physiology of hearing pathways are highly conserved between fish and humans [23]. (2) Zebrafish can be tested rapidly for hearing loss by C-start, a stereotypical behavioural response amenable to high throughput assays [24]. (3) Researchers first identified that the key protein TMIE is important in the mechanoelectrical (MET) channel by using zebrafish [25], and the mechanism of DFNB63 non-syndromic hearing loss was also discovered using zebrafish [26].…”