Imerslund‐Gräsbeck Anemia

Broch, H; Imerslund, Olga; Monn, E; Hovig, Torstein; Seip, M

doi:10.1111/j.1651-2227.1984.tb09937.x

Cited by 66 publications

(18 citation statements)

References 9 publications

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“…The reverse conclusion is therefore that patients with IGS who have proteinuria should have mutations that either affect general expression or the interaction with amnionless or lead to cubilin truncation. According to the literature, such patients do not seem to present with renal insufficiency (13,(37)(38)(39), which is in agreement with the isolated proteinuria cases described here. Functional studies have also shown that vitamin B12 uptake is maintained when the receptor is truncated after CUB8 (40), consistent with the presence of a putative intestinal transcript truncated directly after CUB8 in the Genotype-Tissue Expression (GTEx) database (41).…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…Patients with IGS were diagnosed based on established criteria [1,13], while the parents were healthy. All the families were allegedly unrelated.…”

Section: Methodsmentioning

confidence: 99%

Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

Beech

Liyanarachchi

Shah

et al. 2011

Orphanet J Rare Dis

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BackgroundImerslund-Gräsbeck syndrome (IGS) was described just over 50 years ago by Olga Imerslund and Ralph Gräsbeck and colleagues. IGS is caused by specific malabsorption of cobalamin (Cbl) due to bi-allelic mutations in either the cubilin gene (CUBN) or the human amnionless homolog (AMN). Mutations in the two genes are commonly seen in founder populations or in societies with a high degree of consanguineous marriages. One particular mutation in AMN, c.208-2A>G, causing an out-of-frame loss of exon 4 in the mRNA, is responsible for some 15% of IGS cases globally. We present evidence that this founder mutation causes a substantial percentage of cases among diverse ethnicities and that the mutation is as old as human civilization.MethodsPartial genotyping indicated a founder event but its presence in diverse peoples of Arabic, Turkish, Jewish, and Hispanic ancestry suggested that the mutation might be recurrent. We therefore studied the flanking sequence spanning 3.5 Mb to elucidate the origin of the haplotype and estimate the age of the mutation using a Bayesian inference method based on observed linkage disequilibrium.ResultsThe mutation's distribution, the size of the shared haplotype, and estimates of growth rate and carrier frequency indicated that the mutation was a single prehistoric event. Dating back to the ancient Middle East around 11,600 BC, the mutation predates the advent of writing, farming, and the monotheistic religions of the region.ConclusionsThis mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East. Thus, rare founder mutations may cause a substantial number of cases, even among diverse ethnicities not usually thought to be related.

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“…MGA1, which is characterized by abnormally large erythroid precursors/erythrocytes and impaired DNA synthesis, results from a deficiency in vitamin B12 (Broch et al, 1984). Previously, 17 families with MGA1 were identified with mutations in cubilin (CUBN), which encodes the intrinsic factor (IF)-vitamin B12 receptor in the small intestine .…”

Section: Introductionmentioning

confidence: 99%

Mouse amnionless, which is required for primitive streak assembly,mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules

et al. 2004

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Impaired primitive streak assembly in the mouse amnionless(amn) mutant results in the absence of non-axial trunk mesoderm, a derivative of the middle region of the primitive streak. In addition, the epiblast of amn mutants fails to increase significantly in size after E7.0, indicating that middle primitive streak assembly is mechanistically tied to the growth of the embryo during gastrulation. Amn, a novel transmembrane protein, is expressed exclusively in an extra-embryonic tissue, visceral endoderm (VE), during the early post-implantation stages. We show that Amn is also expressed in kidney proximal tubules (KPT) and intestinal epithelium,which, like the VE, are polarized epithelia specialized for resorption and secretion. To explore whether Amn participates in the development or function of KPT and intestinal epithelia and to gain insight into the function of Amn during gastrulation, we constructed Amn-/- ES cell↔+/+blastocyst chimeras. While chimeras form anatomically normal kidneys and intestine, they exhibit variable, selective proteinuria, a sign of KPT malfunction. In humans, AMN has been genetically connected to Cubilin(CUBN), a multi-ligand scavenger receptor expressed by KPT, intestine and yolk sac. Loss of CUBN, the intestinal intrinsic factor (IF)-vitamin B12 receptor, results in hereditary megaloblastic anemia (MGA1), owing to vitamin B12 malabsorption. The recent report of MGA1 families with mutations in AMN suggests that AMN functions in the same pathway as CUBN. We demonstrate that Cubn is not properly localized to the cell surface in Amn-/- tissues in the embryo and adult mouse, and that adult chimeras exhibit selective proteinuria of Cubn ligands. This study demonstrates that Amn is an essential component of the Cubn receptor complex in vivo and suggests that Amn/Cubn is required for endocytosis/transcytosis of one or more ligands in the VE during gastrulation to coordinate growth and patterning of the embryo. Furthermore, as AMN is apparently not required for gastrulation in humans, the developmental requirements for Amn/Cubn function may not be evolutionarily conserved, possibly reflecting differences between species in the role and organization of extra-embryonic tissues.

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Imerslund‐Gräsbeck Anemia

Cited by 66 publications

References 9 publications

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

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

Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

Mouse amnionless, which is required for primitive streak assembly,mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules

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