Dent disease (DD) is an endocytosis defect characterized by proximal tubule dysfunction. About 60% (DD1) and 15% (DD2) of the patients have mutations in the CLCN5 and OCRL genes. ClC-5 is a Cl-/H+-exchanger functionally linked with the proton pump V-ATPase. Using a Drosophila approach, we showed that silencing the fly orthologues of ClC-5 and ATP6AP2, a V-ATPase subunit, in epithelial cells causes similar phenotypes.
The ATP6AP1and ATP6AP2 accessory subunits, located on the X chromosome, were analyzed by Sanger sequencing in 50 patients without molecular diagnosis of DD.
Twenty patients presented variations in ATP6AP1 and ATP6AP2 genes, about half of them carried more than 1 variant. Nine different variants in ATP6AP1 and five different variants in ATP6AP1were detected in 19 and 13 patients respectively. In two patients we found an inframe insertion of two Alanines into a stretch of nine Alanines encoded by ATP6AP1exon 1. This variant was not detected in the 1000 genome project. Patient phenotype showed syndromic manifestations more severe than DD2 and milder than Lowe syndrome. Clinical diagnosis of Donnai Barrow syndrome, due to loss of function mutations in the LRP2 gene encoding for the megalin receptor, was made but no LRP2 mutation was found. He also presented three OCRL non-coding variants, one which was predicted to be disease-causing. Dysfunction of V-ATPase might have contributed to worsen DD2 phenotype. The second patient was clinically re-evaluated in the light of molecular findings. His main symptoms were nephrolithiasis and nephrocalcinosis. Tubular dysfunction was manifested mainly as hypophosphatemia rather than LMWP. He had renal acidosis; dysfunction of V-ATPase might be responsible of the altered urinary acidification.
Although no clear Dent disease-causing mutation was identified in our patients, variants in these two genes might be considered as modifiers in DD1 and DD2 patients for explaining the phenotypic heterogeneity which characterizes the disease.