<i>ATP6V1C1</i> deficiency impairs auditory and vestibular hair cell function and leads to sensorineural hearing loss in humans and mice

Qingyue Yuan; Hao Zheng; Jun Xu; Yun Lin; Jingyu Liu; Hu Peng; Ningning Yuan; Xiaofei Zheng; Hao Wu; Xiuhong Pang; Tao Yang

doi:10.1016/j.jgg.2026.01.005

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ATP6V1C1 deficiency impairs auditory and vestibular hair cell function and leads to sensorineural hearing loss in humans and mice

doi: 10.1016/j.jgg.2026.01.005

Qingyue Yuan^a,b,c,
Hao Zheng^d,
Jun Xu^a,b,c,
Yun Lin^a,b,c,
Jingyu Liu^a,b,c,
Hu Peng^e,
Ningning Yuan^a,b,c,
Xiaofei Zheng^a,b,c,
Hao Wu^a,b,c,
Xiuhong Pang^f,
Tao Yang^a,b,c

a. Department of Otolaryngology–Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China;
b. Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China;
c. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200011, China;
d. Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Clinical Medical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, China;
e. Department of Otolaryngology-Head and Neck Surgery, Changzheng Hospital, Naval Medical University, Shanghai 201209, China;
f. Department of Otorhinolaryngology-Head and Neck Surgery, the Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu 225300, China

Funds:

This work is supported by grants from National Science Foundation of China (82271157 to TY), Medical Research project of Health Commission of Jiangsu Province (M2022067 to XP), Natural Science Foundation of Taizhou City (TZ202505 to XP), Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine (JYYC013 to TY), Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases (14DZ2260300 to HW), and the Shanghai Top Research Center construction Project (2023ZZ02008 to HW).

Received Date: 2025-08-04
Accepted Date: 2026-01-08
Rev Recd Date: 2026-01-07

Available Online: 2026-01-15

Abstract

Abstract

Multiple genes encoding v-ATPase subunits are associated with various forms of syndromic hearing loss. Their functions in hair cells, the key sensory cells required for hearing and balance, remain unclear. In this study, linkage analysis and exome sequencing of a large autosomal dominant family with non-syndromic deafness identify a pathogenic p.R281P variant in ATP6V1C1 that encodes the C1 subunit of the v-ATPase. Conditional knock-out (CKO) of Atp6v1c1 in mouse hair cells results in early-onset sensorineural hearing loss and vestibular malfunction. The CKO mice show synaptic defects in inner hair cells, evidenced by decreased wave I amplitude and prolonged latency of the auditory brainstem responses, loss of inner hair cell ribbon synapses, accumulation of endocytic compartments, and absence of F-actin mesh network surrounding the active zones. The cochlear and vestibular hair cells of the CKO mice also undergo disrupted autophagic flux and apoptosis. The Atp6v1c1 p.R281P knock-in mice develop late-onset, high-frequency hearing loss with normal hair cell morphology but degenerated spiral ganglion neurons due to disrupted autophagic flux and apoptosis. Our study reveals ATP6V1C1 as a causative gene for non-syndromic deafness and its important roles in maintenance and synaptic function of hair cells.
- ATP6V1C1,
- autophagic flux,
- non-syndromic deafness,
- hair cell,
- synaptic transmission

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References

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