Beyond the tubule: Pathogenic variants in LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR). Due to the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in DB/FOAR patients. We analyzed glomerular filtration rate (GFR) in mice by FITC-inulin clearance and clinically characterized six families including nine DB/FOAR patients and nine family members. Urine samples from patients were analyzed by western blotting and biopsy material by histology. In the mouse model, we used histologic methods to assess nephrogenesis and post-natal renal structure, and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin deficient mice, we found a lower GFR and an increase in the abundance of injury markers such as kidney injury molecule-1 and NAGase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease and glomerular proteinuria early in life. The megalin deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction as present in DB/FOAR syndrome confers an increased risk of progression into chronic kidney disease.