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

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  • Julia Flemming, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Maike Marczenke, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Ina Maria Rudolph, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Rikke Nielsen
  • Tina Storm
  • ,
  • Erik Ilsø Christensen
  • Sebastian Diecke, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Francesco Emma, IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • ,
  • Thomas E. Willnow

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.

Original languageEnglish
Book seriesKidney International
Volume98
Issue1
Pages (from-to)159-167
Number of pages9
ISSN0085-2538
DOIs
Publication statusPublished - 2020

    Research areas

  • endocytosis, low-molecular-weight proteinuria, proximal tubule dysfunction, renal Fanconi syndrome

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