CCDC158: A novel regulator in renal proximal tubular endocytosis unveiled through exome sequencing and interactome analysis.

Renal proximal tubular reabsorption of proteins and polypeptides is tightly regulated by a concerted action of the multi-ligand receptors with subsequent processing from the clathrin-coated pits to early/recycling and late endosomes and towards lysosomes. We performed whole exome-sequencing in a male patient from a consanguineous family, who presented with low- and intermediate molecular weight proteinuria, nephrocalcinosis and oligospermia. We identified a new potential player in tubular endocytosis, coiled-coil domain containing 158 (CCDC158). The variant in CCDC158 segregated with the phenotype and was also detected in a female sibling with a similar clinical kidney phenotype. We demonstrated the expression of this protein in kidney tubules and modeled its structure in silico. We hypothesized that the protein played a role in the tubular endocytosis by interacting with other endocytosis regulators, and used mass spectrometry to identify potential interactors. The role of CCDC158 in receptor-mediated endocytosis was further confirmed by transferrin and GST-RAP trafficking analyses in patient-derived proximal tubular epithelial cells. Finally, as CCDC158 is known to be expressed in the testis, the presence of oligospermia in the male sibling further substantiated the pathogenic role of the detected missense variant in the observed phenotype. In this study, we provide data that demonstrate the potential role of CCDC158 in receptor-mediated endocytosis, most likely by interaction with other endocytosis-related proteins that strongly correlate with the proximal tubular dysfunction phenotype as observed in the patients. However, more studies are needed to fully unravel the molecular mechanism(s) in which CCDC158 is involved.