Christer, S., Marelja, Z., Dibra, I., Hauschild, H., Berquez, M., Gandhi, H., Shih, Y.H., Keller, S., Helmstädter, M., Schell, C., Devuyst, O., Simons, M. (2026). A Drosophila model for Dent's disease type 1 revealed impaired endoplasmic reticulum export of Cubilin as pathogenic mechanism.  Kidney Int. 109(5): 957--970.

FBrf0265224

Research paper

Pathogenic variants in the CLCN5 gene encoding the chloride-hydrogen exchanger ClC-5 cause Dent's disease type 1, a genetic disorder of the endolysosomal pathway in the proximal tubules of the kidneys. A hallmark of this disease is the downregulation of the protein uptake receptor consisting of megalin, cubilin and amnionless, causing low-molecular-weight proteinuria. Why these receptors are downregulated is not fully understood. To clarify this, we established an in vivo model for Dent's disease using Drosophila nephrocytes that share similarities with podocytes and proximal tubule cells. Dissected nephrocytes were subjected to immunostaining, uptake tracer studies and transmission electron microscopy. Additionally, histological analysis, immunostainings and Western blotting were performed on Clcn5[Y/-] mice. Upon depletion of ClC-c, the fly ortholog of CLCN5, Cubilin was lost from the plasma membrane of nephrocytes, leading to a strong decrease in albumin uptake and ectopic slit diaphragms. Importantly, Cubilin exhibited a strong accumulation in the endoplasmic reticulum, while its binding partner Amnionless was overall reduced. This was accompanied by a fragmentation of the endoplasmic reticulum (ER) morphology and an increase in ER exit sites and associated Golgi stacks. Additionally, the actin and microtubular cytoskeleton as well as recycling endosomes showed a strong cortical accumulation, whereas cholesterol-enriched autophagic compartments emerged in the perinuclear area. Similar phenotypes were observed upon silencing of the C subunit of the vacuolar proton-ATPase (V-ATPase), suggesting they might depend on defects in acidification and glycosylation in the Golgi apparatus. Amnionless loss and ER retention of cubilin was confirmed in ClC-5 knockout mice, underscoring the relevance of this pathomechanism for Dent's disease. Our findings suggest that in addition to its endosomal role ClC-c/ClC-5 acts in the secretory pathway to promote surface trafficking of the Cubilin/Amnionless complex. This function may partly explain low-molecular-weight proteinuria in patients with Dent's disease.