Ncoa7, or nuclear receptor coactivator 7, is a protein-coding gene. It is a member of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family. Ncoa7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase, playing a crucial role in normal assembly and activity of this proton pump, which is essential for lysosomal function, endolysosomal homeostasis, and is involved in multiple biological processes like neurodevelopment and behaviour [1].

In gene knockout (KO) mouse models, targeted deletion of the Ncoa7 gene led to incomplete distal renal tubular acidosis (dRTA) in mice. Ncoa7 KO mice showed a persistently high urine pH and developed hypobicarbonatemia after acid loading, with reduced abundance of several V-ATPase subunits in medullary intercalated cells, suggesting Ncoa7's importance in maintaining proteins related to kidney acid-base regulation [3]. Also, Ncoa7 deletion in animals led to abnormal neuronal patterning defects, reduced expression of lysosomal markers, and exhibited anxiety and social defects in mice, highlighting its role in neurodevelopment [1]. In endothelial cells, Ncoa7 deficiency produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes and worsening pulmonary arterial hypertension (PAH) in mice [2,4].

In summary, Ncoa7 is vital for normal V-ATPase function, which impacts lysosomal function, endolysosomal homeostasis, and is essential for neurodevelopment and kidney acid-base regulation. The Ncoa7 KO mouse models have revealed its role in diseases such as dRTA, PAH, and neurodevelopmental disorders, providing valuable insights into the underlying molecular mechanisms.

References:

1. Castroflorio, Enrico, den Hoed, Joery, Svistunova, Daria, Davies, Benjamin, Oliver, Peter L. 2020. The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour. In Cellular and molecular life sciences : CMLS, 78, 3503-3524. doi:10.1007/s00018-020-03721-6. https://pubmed.ncbi.nlm.nih.gov/33340069/

2. Harvey, Lloyd D, Alotaibi, Mona, Tai, Yi-Yin, Jain, Mohit, Chan, Stephen Y. 2025. Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension. In Science (New York, N.Y.), 387, eadn7277. doi:10.1126/science.adn7277. https://pubmed.ncbi.nlm.nih.gov/39847635/

3. Merkulova, Maria, Păunescu, Teodor G, Nair, Anil V, Breton, Sylvie, Brown, Dennis. 2018. Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice. In American journal of physiology. Renal physiology, 315, F173-F185. doi:10.1152/ajprenal.00407.2017. https://pubmed.ncbi.nlm.nih.gov/29384414/

4. Harvey, Lloyd D, Alotaibi, Mona, Kim, Hee-Jung Janice, Jain, Mohit, Chan, Stephen Y. 2024. Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.02.26.582142. https://pubmed.ncbi.nlm.nih.gov/38464060/