Kidney Int

. 2020 Jul;98(1):159-167. doi: 10.1016/j.kint.2020.02.021. Epub 2020 Mar 24. https://pubmed.ncbi.nlm.nih.gov/32471643/

Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Julia Flemming ¹, Maike Marczenke ¹, Ina-Maria Rudolph ¹, Rikke Nielsen ², Tina Storm ², Ilsoe Christensen Erik ², Sebastian Diecke ¹, Francesco Emma ³, Thomas E Willnow ⁴Affiliations expand

• PMID: 32471643
• PMCID: PMC7322522
• DOI: 10.1016/j.kint.2020.02.021

Free PMC article

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.

Keywords: endocytosis; low-molecular-weight proteinuria; proximal tubule dysfunction; renal Fanconi syndrome.

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