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


Autoři: Luping Zhang aff001;  Yu Gao aff001;  Ru Zhang aff002;  Feifei Sun aff001;  Cheng Cheng aff003;  Fuping Qian aff001;  Xuchu Duan aff001;  Guanyun Wei aff001;  Cheng Sun aff001;  Xiuhong Pang aff004;  Penghui Chen aff005;  Renjie Chai aff001;  Tao Yang aff005;  Hao Wu aff005;  Dong Liu aff001
Působiště autorů: Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital, School of Life Science, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China aff001;  Shanghai East Hospital, Department of Otorhinolaryngology Shanghai, Shanghai, China aff002;  Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China aff003;  Department of Otorhinolaryngology-Head and Neck Surgery, Taizhou People’s Hospital, Fifth Affiliated Hospital, Nantong University, Taizhou, China aff004;  Department of Otorhinolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China aff005;  Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China aff006;  Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China aff007
Vyšlo v časopise: THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008953
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008953

Souhrn

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.

Klíčová slova:

Apoptosis – Confocal microscopy – DAPI staining – Deafness – Fluorescence imaging – Linkage analysis – Messenger RNA – Zebrafish


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