Failure of endocytic flux in Donnai-Barrow Syndrome caused by LRP2 p.C1400R

Andrew Beenken; Tian H. Shen; Aryan Ghotra; Hediye Erdjument-Bromage; Jeong Lee; Jared S. Kushner; Rachel E. Sturley; Atlas Khan; Jeffrey R. Arace; Leora Kronenberg; Lucy D. Shen; Gabriel H. Rahmani; Patricia K. Donahoe; Thomas A. Neubert; Frances A. High; Ora A. Weisz; Jonathan Barasch

doi:10.1172/jci.insight.199341

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Beenken, A. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Shen, T. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Ghotra, A. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Erdjument-Bromage, H. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Lee, J. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Kushner, J. in: PubMed | Google Scholar |

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Sturley, R. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Khan, A. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Arace, J. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Kronenberg, L. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Shen, L. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Rahmani, G. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Donahoe, P. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Neubert, T. in: PubMed | Google Scholar |

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by High, F. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Weisz, O. in: PubMed | Google Scholar

¹Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

²Department of Neuroscience, NYU Grossman School of Medicine, New York, United States of America

³Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States of America

⁴Pediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America

⁵Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

Find articles by Barasch, J. in: PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.199341.
Copyright © 2026, Beenken et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 23, 2026 - Version history

Donnai-Barrow Syndrome (DBS) arises from loss-of-function (LoF) variants in the endocytic receptor LRP2/megalin and is characterized by low molecular weight (LMW) proteinuria and developmental abnormalities. Urinary proteomics of nine DBS patients revealed that the urinary proteome of a DBS patient with the missense variant LRP2 p.C1400R was indistinguishable from that of patients with splice site, nonsense, or frameshift mutations. A CRISPR mouse model of the variant was generated to determine the mechanism of LoF and proteinuria. The mutant LRP2 was expressed and observed to dimerize and localize to the proximal tubule apical membrane. However, both fluid-phase and receptor-mediated endocytosis were impaired in the context of a general perturbation of endocytic flux. Immunofluorescence revealed aberrant endocytic recycling with mislocalized RAB11⁺ and TFR1⁺ compartments and enlarged lysosomes. Structural modeling showed the LRP2 assembly likely tolerates the cysteine to arginine substitution at the cell surface, but at endosomal pH the variant introduced steric clashes that may disrupt intramolecular interfaces and disturb receptor recycling. These findings point to the importance of LRP2 recycling for global endocytic flux and offer a blueprint for leveraging patient-specific alleles to dissect proximal tubule function.

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Failure of endocytic flux in Donnai-Barrow Syndrome caused by LRP2 p.C1400R

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