2015
DOI: 10.1007/s00467-014-3037-7
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In-depth phenotyping of a Donnai–Barrow patient helps clarify proximal tubule dysfunction

Abstract: Background The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/ FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. Clinical case A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination wa… Show more

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Cited by 29 publications
(27 citation 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%
“…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%
“…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%
“…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%