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Kidney Week

Abstract: TH-PO814

Studying the Link Between Nephropathic Cystinosis and Tubular Acidosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Jamalpoor, Amer A., Utrecht Institute of Pharmaceutical Sciences, Utrecht, Netherlands
  • van Eerde, Albertien M., Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
  • Lilien, Marc, Wilhelmina Children's Hosp Univ Med Ctr, Utrecht, Netherlands
  • Zaal, Esther A., Utrecht University, Utrecht, Netherlands
  • Berkers, Celia, Utrecht University, Utrecht, Netherlands
  • Masereeuw, Rosalinde, Utrecht Institute for Pharmaceutical Sciences, Utrecht,, Utrecht, Netherlands
  • Janssen, Manoe J., Utrecht University, Utrecht, Netherlands

Group or Team Name

  • Roos Masereeuw-group

Recently, a 23-month old girl presented with rickets, metabolic acidosis, signs of renal Fanconi syndrome and increased granulocyte cystine levels. The suspected diagnosis was cystinosis, a disease caused by mutations in the CTNS gene (cystine transporter), leading to the lysosomal accumulation of cystine, causing organ damage, particularly the kidneys. However, genetic testing revealed no mutation in CTNS, but compound heterozygous pathogenic mutations in the ATP6V1B1 gene. ATP6V1B1 encodes the B1 subunit of the lysosomal V1 ATPase, which is deficient in distal renal tubular acidosis type 1B, but with an unknown link to cystinosis. The present study aimed to determine the link between renal tubular acidosis and nephropathic cystinosis.


CRISPR/Cas9 technology was used to knock-out the ATP6V1B1 gene in conditionally immortalized proximal tubular epithelial cells (ciPTEC) and cell characteristics were compared to isogenic CTNS-/- cells. An untargeted metabolomics approach based on UHPLC-MS/MS was applied for the intracellular quantification of metabolites differentially expressed in knock-out and control cells. Fluorescence-based imaging assays were applied to monitor the lysosomal-autophagy dynamics (TFEB, LC3, and DQ-BSA) in ciPTEC.


The ATP6V1B1-/- isogenic ciPTEC showed a significant increase in cystine accumulation compared to healthy control cells (0.26 vs. 0.13 nmol/mg protein; p<0.05). But this was significantly lower as compared to cystine accumulation in CTNS-/- cells (6.32 vs. 0.26 nmol/mg protein; p<0.05). Like the CTNS-/- cells, ATP6V1B1-/- cells demonstrated an abnormally increased autophagy as shown by the increased TFEB nuclear translocation (2-fold; p<0.05), increased accumulation of LC3 (2.3-fold; p<0.05), and increased lysosomal degradation of DQ-BSA (2-fold; p<0.05). Moreover, using metabolomics, we identified several metabolites and pathways that were altered (p<0.05) in both renal acidosis and cystinotic cells.


We successfully developed a new genetically engineered renal tubular acidosis cell model with isogenic controls. These cells provide a novel versatile tool to study the pathology of renal tubular acidosis. Metabolomics allowed us to bridge the gap between cystinosis and renal acidosis, with the future aim of finding druggable targets.


  • Government Support - Non-U.S.