Article (Scientific journals)
Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.
Charlton, Jennifer R.; Tan, Weizhen; Daouk, Ghaleb et al.
2020In American Journal of Physiology. Renal Physiology, 319 (6), p. 988-F999
Peer Reviewed verified by ORBi


Full Text
Publisher postprint (2.38 MB)
Request a copy

All documents in ORBi are protected by a user license.

Send to


Keywords :
Adolescent; Adult; Animals; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Kidney Glomerulus/pathology; Low Density Lipoprotein Receptor-Related Protein-2/genetics/metabolism; Male; Mice; Mice, Knockout; Middle Aged; Renal Insufficiency, Chronic/genetics/pathology; Young Adult; cationic ferritin-enhanced magnetic resonance imaging; glomerular number; kidney disease etiology; megalin; nephron loss; proximal tubule
Abstract :
[en] 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.
Disciplines :
Urology & nephrology
Author, co-author :
Charlton, Jennifer R.
Tan, Weizhen
Daouk, Ghaleb
Teot, Lisa
Rosen, Seymour
Bennett, Kevin M.
Cwiek, Aleksandra
Nam, Sejin
Emma, Francesco
Jouret, François  ;  Université de Liège - ULiège > Cardiovascular Sc.-Lab. of Translational Res. in Nephrology
Oliveira, João Paulo
Tranebjærg, Lisbeth
Frykholm, Carina
Mane, Shrikant
Hildebrandt, Friedhelm
Srivastava, Tarak
Storm, Tina
Christensen, Erik Ilsø
Nielsen, Rikke
More authors (9 more) Less
Language :
Title :
Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.
Publication date :
Journal title :
American Journal of Physiology. Renal Physiology
Publisher :
American Physiological Society, Bethesda, United States - Maryland
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 22 December 2020


Number of views
27 (2 by ULiège)
Number of downloads
2 (2 by ULiège)

Scopus citations®
Scopus citations®
without self-citations


Similar publications

Contact ORBi