Flemming, J;
Marczenke, M;
Rudolph, I-M;
Nielsen, R;
Storm, T;
Erik, IC;
Diecke, S;
... Willnow, TE; + view all
(2020)
Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome.
Kidney International
, 98
(1)
pp. 159-167.
10.1016/j.kint.2020.02.021.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.kint.2020.02.021 |
| Publisher version: | https://doi.org/10.1016/j.kint.2020.02.021 |
| Language: | English |
| Additional information: | Copyright © 2020, International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | endocytosis, low-molecular-weight protein, uria, proximal tubule dysfunction, renal Fanconi syndrome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10110951 |
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