A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity

The ATP6V0A4 gene encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2025-04-29
DOI
https://doi.org/10.1172/jci188807
Citations
4
Primary Topic
ATP Synthase and ATPases Research
Type
article
Field-Weighted Citation Impact
3.22

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity

Hong Fan, Jianlu Wei, Chengkun Wang, Ting-song Li et al.
4 citations
Journal of Clinical Investigation
ATP Synthase and ATPases Research
3.22
article

A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity

Hong Fan, Jianlu Wei, Chengkun Wang, Ting-song Li, Wanyi Wang, Qianqian Wu, Zhi-Yuan Wei, Rong Zhou, Wen Shi, Jun Liao, Jiayuan Sun, Peng Sun, Hui Cai, Xiaoliang Zhang, Xin‐Hua Li, Bin Wang, Yuan‐Han Yang, Yilin Zhang, Lu Huang, Bi-Cheng Liu, Junlan Yang, Xiaoxu Wang
article en
4 citations

Abstract

The ATP6V0A4 gene encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.

Journal of Clinical InvestigationVol. 135(13)
Emory University (US), Sun Yat-sen University (CN), China Pharmaceutical University (CN), Ministry of Education (RO), Zhongda Hospital Southeast University (CN), Third Affiliated Hospital of Sun Yat-sen University (CN), Children's Hospital of Chongqing Medical University (CN), Southeast University (CN), Nanjing Medical University (CN), Chongqing Medical University (CN)
Jiangsu Commission of Health, National Natural Science Foundation of China, Government of Jiangsu Province, Nanjing Medical University, Southeast University, Jiangsu Provincial Key Research and Development Program, Changjiang Scholar Program of Chinese Ministry of Education, National Key Research and Development Program of China
Openalex Percentile: Top 9%
ATP Synthase and ATPases Research
3.22
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.