Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease
Year: 2020
Type: article
Abstract: 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) syndrome. Because of 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 patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-β-d-glucosaminidase. 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. 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.
Authors: Jennifer R. Charlton, Weizhen Tan, Ghaleb Daouk, Lisa Teot, Seymour Rosen, Kevin M. Bennett, Aleksandra Cwiek, Sejin Nam, Francesco Emma, François Jouret, João Paulo Oliveira, Lisbeth Tranebjærg, Carina Frykholm, Shrikant Mane, Friedhelm Hildebrandt, Tarak Srivastava, Tina Storm, Erik Ilsø Christensen, Rikke Nielsen
Institutions: University of Virginia, Massachusetts General Hospital, Boston Children's Hospital, Beth Israel Deaconess Medical Center, Washington University in St. Louis, University of Hawaiʻi at Mānoa, Bambino Gesù Children's Hospital, University of Liège, Universidade do Porto, Hospital de São João, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, University of Copenhagen, Rigshospitalet, Kennedy Center, Uppsala University, Yale University, Harvard University, Children's Mercy Hospital, Aarhus University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Yale University, Sundhed og Sygdom, Det Frie Forskningsråd, Novo Nordisk, Augustinus Fonden, Uniwersytet Warszawski, National Institutes of Health, Medical Research Council, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1044130170, G2274654633, G3245471538, G4034409254, G4110880326, G5130874134, G5183736941, G5926434626, 9.4 Tesla MR Scanner for Murine Imaging, George M. O'Brien Kidney Center at Yale, Discover and functionally characterize full-penetrance causes of nephrosis / FSGS, G9000045419, G9000062737, G9000323323, Yale Clinical and Translational Science Award
OpenAlex ID: W3093988292