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The lysosomal V-ATPase B1 subunit in proximal tubule is linked to nephropathic cystinosis

Background Recently, a 23-month-old girl presented with increased granulocyte cystine levels, metabolic acidosis and symptoms of renal Fanconi syndrome. Cystinosis was suspected and treatment with electrolytes and cysteamine, a cystine depleting agent, was started that appeared effective. However, genetic testing did not detect any variants in CTNS (the gene affected in cystinosis) but instead revealed pathogenic variants in ATP6V1B1. ATP6V1B1 encodes the B1 subunit of the vacuolar H+-ATPase (V-ATPase), that is linked to autosomal recessive distal renal tubular acidosis, a metabolic disorder with an inappropriately alkaline urine and deafness. Here, the unknown link between ATP6V1B1 gene deficiency and proximal tubulopathy as well as a possible link to cystinosis pathophysiology was investigated. Methods We used CRISPR/Cas9 technology to selectively knockout the ATP6V1B1 or CTNS gene in human renal proximal tubule cells and compare their proteomic and metabolomic profile with isogenic wild type proximal tubule cells. Results ATP6V1B1 was expressed along the human distal but also the proximal segments of the nephron. Consistent with the clinical data, loss of ATP6V1B1 in renal proximal tubule cells resulted in increased cystine levels with autophagy activation. Further, omics profiling showed that both ATP6V1B1-/- and CTNS-/- cells are in metabolic acidosis with impaired autophagy and signs of proximal tubular epithelial dysfunction. Conclusion We identified the lysosomal V-ATPase B1 subunit to play an important role in proximal tubule function, regulating cystine transport and autophagy in human renal proximal tubule cells through its interaction with cystinosin and mTOR-signaling.