Evidence map›Paper›PMID 42024452›Full record

ArticleJCI insight2026

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 and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JCI insight, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Megalin: from structure to function.Nature reviews. Nephrology · 2026
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Andrew BeenkenDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Tian H ShenDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Aryan GhotraDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Hediye Erdjument-BromageDepartment of Neuroscience, NYU Grossman School of Medicine, New York, New York, USA.
Jeong LeeDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Jared S KushnerDivision of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Rachel E SturleyDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Atlas KhanDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Jeffrey R AraceDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Leora KronenbergDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Lucy D ShenDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Gabriel H RahmaniDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Patricia K DonahoePediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Thomas A NeubertDepartment of Neuroscience, NYU Grossman School of Medicine, New York, New York, USA.
Frances A HighPediatric Surgical Research Laboratories and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Ora A WeiszRenal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Jonathan BaraschDivision of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.

Funding

Endocytic Pathway Dysfunction in Dent DiseaseR01DK125049 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI WEISZ, ORA A · 2020 to 2024
$2.3M
Structural regulation of megalin recycling in the proximal tubuleK08DK132511 · NIDDK · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ANDREW S BEENKEN · 2023 to 2026
$666k
NIDDK NIH HHS K08 DK132511NIDDK NIH HHS R01 DK125049
6 · The paper itself

Abstract

Donnai-Barrow syndrome (DBS) arises from loss-of-function (LoF) variants in the endocytic receptor low-density lipoprotein receptor-related protein 2 (LRP2; or megalin) and is characterized by low-molecular weight proteinuria and developmental abnormalities. Urinary proteomics of 9 patients with DBS 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 was 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 that 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.

Indexed as

Agenesis of Corpus CallosumEndocytosisLow Density Lipoprotein Receptor-Related Protein-2ProteinuriaRenal Tubular Transport, Inborn ErrorsAnimalsDisease Models, AnimalFemaleHearing Loss, SensorineuralHernias, Diaphragmatic, CongenitalHumansKidney Tubules, ProximalLoss of Function MutationMaleMiceMyopiaLow Density Lipoprotein Receptor-Related Protein-2LRP2 protein, humanLrp2 protein, mouseCell biologyGenetic diseasesNephrologyProtein trafficProteomics

Identifiers

PMID42024452
PMCPMC13313491

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.