Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7

Namour, Farès; Dobrovoljski, Gabriele; Chéry, Céline; Audonnet, Sandra; Feillet, François; Sperl, Wolfgang; Guéant, Jean Louis

doi:10.3324/haematol.2011.043984

Cited by 25 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The proteinuria is generally believed to be "benign" with preservation of kidney function over time (68), although minor, glomerular changes have been described (26,47). In contrast to most reported cases (23,26,27,47,67,74,84,107,125,178), patients harboring a particular CUBN Following receptor-mediated endocytosis via apical coated pits, the complexes accumulate in lysosomes for degradation of the proteins, whereas the receptors including AMN recycle to the apical plasma membrane via dense apical tubules. As illustrated here and detailed in the text, megalin mediates the uptake of cubilin and its ligands.…”

Section: Signalingmentioning

confidence: 99%

Endocytic Receptors in the Renal Proximal Tubule

et al. 2012

View full text Add to dashboard Cite

Protein reabsorption is a predominant feature of the renal proximal tubule. Animal studies show that the ability to rescue plasma proteins relies on the endocytic receptors megalin and cubilin. Recently, studies of patients with syndromes caused by dysfunctional receptors have supported the importance of these for protein clearance of human ultrafiltrate. This review focuses on the molecular biology and physiology of the receptors and their involvement in renal pathological conditions.

show abstract

Section: Signalingmentioning

confidence: 99%

Endocytic Receptors in the Renal Proximal Tubule

et al. 2012

View full text Add to dashboard Cite

show abstract

“…We and others have demonstrated a highly interdependent relationship of cubilin and amnionless for correct processing and apical trafficking to the plasma membrane [ 14 , 17 - 24 ]. So far, no transmembrane segment or endocytic signals have been identified in cubilin [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome

et al. 2013

View full text Add to dashboard Cite

BackgroundImerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria.MethodsGenetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype.ResultsGenetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed.ConclusionsIn the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.

show abstract

“…Despite multiple studies reported in cells, 15 , 16 , 17 mice, 18 , 19 , 20 , 21 rats, 22 , 23 and dogs, 24 , 25 very little is known about the role of megalin and cubilin in humans. 26 , 27 Available data rely on the phenotypes of rare genetic diseases resulting in dysfunctional megalin (Dent’s disease, 28 , 29 , 30 Lowe’s syndrome, 28 , 29 and Donnai-Barrow syndrome 5 , 31 , 32 , 33 , 34 ) or cubilin (Imerslund–Gräsbeck syndrome 35 , 36 , 37 , 38 and Fanconi-bichel syndrome 39 ). However, it remains unclear how normal megalin and cubilin respond to increased protein load in common human kidney diseases.…”

mentioning

confidence: 99%

Proximal Tubular Expression Patterns of Megalin and Cubilin in Proteinuric Nephropathies

Sun

Hultenby

Axelsson

et al. 2017

Kidney International Reports

View full text Add to dashboard Cite

IntroductionReceptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubules. For albumin this process involves at least 2 interacting receptors, megalin and cubilin. Albumin is not usually present in the urine, indicating a highly efficient tubular reuptake under physiological conditions. However, early appearance of albuminuria may mean that the tubular system is overwhelmed by large quantities of albumin or that the function is impaired.MethodsTo better understand the physiological role of megalin and cubilin in human renal disease, renal biopsies from 15 patients with a range of albuminuria and 3 healthy living donors were analyzed for proximal tubular expression of megalin and cubilin using immunohistochemistry (IHC) and semiquantitative immune-electron microscopy. Their expression in proteinuric zebrafish was also studied.ResultsMegalin and cubilin were expressed in brush border and cytoplasmic vesicles. Patients with microalbuminuric IgA nephropathy and thin membrane disease had significantly higher megalin in proximal tubules, whereas those with macro- or nephrotic-range albuminuria had unchanged levels. Cubilin expression was significantly higher in all patients. In a proteinuric zebrafish nphs2 knockdown model, we found a dose-dependent increase in the expression of tubular megalin and cubilin in response to tubular protein uptake.DiscussionMegalin and cubilin show different expression patterns in different human diseases, which indicates that the 2 tubular proteins differently cooperate in cleaning up plasma proteins in kidney tubules.

show abstract

Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7

Cited by 25 publications

References 25 publications

Endocytic Receptors in the Renal Proximal Tubule

Endocytic Receptors in the Renal Proximal Tubule

Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome

Proximal Tubular Expression Patterns of Megalin and Cubilin in Proteinuric Nephropathies

Contact Info

Product

Resources

About