Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome.
endocytosis
low-molecular-weight proteinuria
proximal tubule dysfunction
renal Fanconi syndrome
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
29
05
2019
revised:
11
02
2020
accepted:
13
02
2020
pubmed:
31
5
2020
medline:
22
6
2021
entrez:
31
5
2020
Statut:
ppublish
Résumé
Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient-derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalin R3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family.
Identifiants
pubmed: 32471643
pii: S0085-2538(20)30263-5
doi: 10.1016/j.kint.2020.02.021
pmc: PMC7322522
pii:
doi:
Substances chimiques
Ligands
0
Low Density Lipoprotein Receptor-Related Protein-2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
159-167Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT098051
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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