In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

Dachy, Angélique; Paquot, François; Debray, Guillaume; Bovy, Christophe; Christensen, Erik; Collard, Laure; Jouret, François

doi:10.1007/s00467-014-3037-7

Cited by 29 publications

(27 citation statements)

References 15 publications

(34 reference statements)

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“…EM analysis of megalin knockout mice showed no gross morphological changes in PT cell structure but revealed dramatic ultrastructural changes in the apical endocytic pathway, including the loss of clathrin-coated pits, endosomes, and lysosomes (18). Similar results were recently reported in a kidney biopsy specimen from a Donnai-Barrow patient harboring a mutation in megalin (86). Additionally, knockout of megalin in zebrafish larvae results in the disappearance of Rab4-positive apical endosomes from the pronephros and impairs the endocytic uptake of both membrane-bound and fluid-phase cargo (87).…”

Section: Organization Of the Proximal Tubule Apical Endocytic Pathwaysupporting

confidence: 90%

Receptor-Mediated Endocytosis in the Proximal Tubule

Eshbach

Weisz

2017

Annu. Rev. Physiol.

128

113

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Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.

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Section: Organization Of the Proximal Tubule Apical Endocytic Pathwaysupporting

confidence: 90%

Receptor-Mediated Endocytosis in the Proximal Tubule

Eshbach

Weisz

2017

Annu. Rev. Physiol.

128

113

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“…2,[8][9][10] By contrast, patients with DBS invariably suffer from renal resorption defects (renal Fanconi syndrome) characterized by urinary loss of megalin ligands, including vitamins D, A, and B12 bound to their plasma carrier proteins. 1,11,12 This observation underscores the central role played by megalin in proximal tubular retrieval processes in humans.…”

mentioning

confidence: 57%

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

Flemming¹,

Marczenke²,

Rudolph³

et al. 2020

Kidney International

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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.

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“…Although not measured in all patients, the proportion of albumin in the urinary protein was higher than 50%, and urinary α1-or β2-microglobulin was mostly low or absent ( Table 1, Supplemental Table 1, and refs. 7, 8), which is in contrast to other forms of tubular proteinuria, including megalin deficiency (12).…”

Section: Introductionmentioning

confidence: 90%

“…One example is Dent's disease, in which mutations in CLCN5 and OCRL1 lead to defective trafficking of the uptake receptor complex (9), consisting of megalin (LRP2), cubilin (CUBN), and amnionless (AMN) (10,11). Whereas mutations in LRP2 cause Donnai-Barrow syndrome, a multisystem developmental disorder (12), CUBN and AMN mutations lead to Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal vitamin B12 malabsorption and, in about half the cases, proteinuria (13). The phenotypes reflect the expression patterns of all 3 proteins: megalin is expressed more broadly, whereas the expression of cubilin and amnionless is mostly limited to the small intestines and kidneys.…”

Section: Introductionmentioning

confidence: 99%

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Bedin¹,

Boyer²,

Servais³

et al. 2019

Journal of Clinical Investigation

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BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding. METHODS. We used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods. RESULTS. We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts. CONCLUSION. Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.

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In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

Cited by 29 publications

References 15 publications

Receptor-Mediated Endocytosis in the Proximal Tubule

Receptor-Mediated Endocytosis in the Proximal Tubule

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

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

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