scholarly journals Imerslund-Grasbeck syndrome- a rare cause of megaloblastic anemia in an infant with homozygous mutation in CUBN gene: a case report and review of the literature

2021 ◽  
Vol 8 (7) ◽  
pp. 1281
Author(s):  
Mehak Agarwal ◽  
Sanmathi Suresh ◽  
Dhaarani Jayaraman ◽  
Sri Gayathri Shanmugam
Keyword(s):  
Vitamin B12 ◽  
Renal Tubule ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Tubular Reabsorption ◽  
Megaloblastic Anaemia ◽  
Nutritional Deficiencies ◽  
Homozygous Mutation ◽  
Review Of The Literature ◽  
Common Causes

Megaloblastic anaemia is one of the important causes of pancytopenia in children and nutritional deficiencies of vitamin B12 and folate are the most common causes comprising 95% of these cases. Defects in absorption, transport and metabolism of vitamin B12 are well described, however, are very rare. We report a rare case of Imersland Grasbeck syndrome, in an infant who presented with pancytopenia, with defective absorption of B12-intrinsic factor complex at the ileum and defective tubular reabsorption of proteins in renal tubule due to same protein defect caused by mutations in two genes – CUBN (cubilin) and AMN (amnionless).

scholarly journals Imerslund-Grasbeck Syndrome: A Case Report

2011 ◽  
Vol 31 (3) ◽  
pp. 249-250
Author(s):  
TN Ghosh ◽  
K Nayek ◽  
A Banerjee
Keyword(s):  
Case Report ◽  
Early Detection ◽  
Vitamin B12 ◽  
Key Words ◽  
Genetic Counselling ◽  
Terminal Ileum ◽  
Autosomal Recessive ◽  
Intrinsic Factor ◽  
Autosomal Recessive Disorder ◽  
Megaloblastic Anaemia

Imerslund-Grasbeck syndrome is a rare autosomal recessive disorder due to selective malabsorption of Vitamin B12 at the level of cobalamin-intrinsic factor receptor mutation in the terminal ileum resulting in megaloblastic anaemia with proteinuria. Early detection of this rare disorder would enable screening and genetic counselling for asymptomatic family members. Key words: Imerslund Grasbeck Syndrome; Megaloblastic anaemia; Proteinuria DOI: http://dx.doi.org/10.3126/jnps.v31i3.5159 J Nep Paedtr Soc 2011;31(3): 249-250

The functional cobalamin (vitamin B12)–intrinsic factor receptor is a novel complex of cubilin and amnionless

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1573-1579 ◽  
Author(s):  
John C. Fyfe ◽  
Mette Madsen ◽  
Peter Højrup ◽  
Erik I. Christensen ◽  
Stephan M. Tanner ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Autosomal Recessive ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Gel Filtration ◽  
Autosomal Recessive Disorder ◽  
Lysosomal Degradation ◽  
Amino Terminal ◽  
Genes Encoding ◽  
Vitamin B12 Malabsorption

Abstract Imerslund-Gräsbeck syndrome (I-GS, megaloblastic anemia 1) is an autosomal recessive disorder characterized by intestinal cobalamin (vitamin B12) malabsorption and proteinuria. I-GS–causing mutations are found in either of 2 genes encoding the epithelial proteins: cubilin and amnionless (AMN). Cubilin recognizes intrinsic factor (IF)–cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively, whereas the function of AMN is unknown. Here we show that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin–binding cubilin construct, neither protein alone conferred ligand endocytosis. In cubilin transfectants, cubilin accumulated in early biosynthetic compartments. However, in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes, and the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF. These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause IG-S.

Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor–vitamin B12 by cubilin

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 405-409 ◽  
Author(s):  
Mette Kristiansen ◽  
Maria Aminoff ◽  
Christian Jacobsen ◽  
Albert de la Chapelle ◽  
Ralf Krahe ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Autosomal Recessive Disorder ◽  
Site Directed Mutagenesis ◽  
Mutant Form ◽  
Wild Type ◽  
Surface Plasmon Resonance Analysis ◽  
Mammalian Expression ◽  
Iodine 125

Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder caused by the selective intestinal malabsorption of intrinsic factor (IF) and vitamin B12/cobalamin (Cbl) in complex. Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B12 receptor, cubilin. By site-directed mutagenesis, mammalian expression, and functional comparison of the purified wild-type and FM1 mutant forms of the IF–Cbl-binding cubilin region (CUB domains 5-8, amino acid 928-1386), we have investigated the functional implications of the P1297L mutation. Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the Kd for IF–Cbl binding several-fold, largely by decreasing the association rate constant. In agreement with the binding data, the wild-type protein, but not the FM1 mutant protein, potently inhibits 37°C uptake of iodine 125–IF–Cbl in cubilin-expressing epithelial cells. In conclusion, the data presented show a substantial loss in affinity of the FM1 mutant form of the IF–Cbl binding region of cubilin. This now explains the malabsorption of Cbl and Cbl-dependent anemia in MGA1 patients with the FM1 mutation.

scholarly journals The Human Intrinsic Factor-Vitamin B12 Receptor,Cubilin: Molecular Characterization and Chromosomal Mapping of the Gene to 10p Within the Autosomal Recessive Megaloblastic Anemia (MGA1) Region

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3593-3600 ◽  
Author(s):  
Renata Kozyraki ◽  
Mette Kristiansen ◽  
Asli Silahtaroglu ◽  
Claus Hansen ◽  
Christian Jacobsen ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Autosomal Recessive ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Recessive Gene ◽  
Proteolytic Processing ◽  
Chromosomal Mapping ◽  
Surface Plasmon Resonance Analysis ◽  
Amino Terminal ◽  
Resonance Analysis

Abstract Uptake of vitamin B12 (cyanocobalamin) is facilitated by the cobalamin-binder gastric intrinsic factor (IF), which recognizes a 460-kD receptor, cubilin, present in the epithelium of intestine and kidney. Surface plasmon resonance analysis of ligand-affinity-purified human cubilin demonstrated a high-affinity calcium- and cobalamin-dependent binding of IF-cobalamin. Complete cDNA cloning of the human receptor showed a 3597 amino acid peripheral membrane protein with 69% identity to rat cubilin. Amino-terminal sequencing of the receptor indicates that the cDNA sequence encodes a precursor protein undergoing proteolytic processing due to cleavage at a recognition site (Arg7-Glu8-Lys9-Arg10) for the trans-Golgi proteinase furin. Using fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones, the human cubilin gene was mapped between the markers D10S1661 and WI-5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia.

scholarly journals Combined congenital deficiencies of intrinsic factor and R binder

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 940-943 ◽  
Author(s):  
J Zittoun ◽  
J Leger ◽  
J Marquet ◽  
R Carmel
Keyword(s):  
Spinal Cord ◽  
Folic Acid ◽  
Vitamin B12 ◽  
Polymorphonuclear Leukocytes ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Serum Vitamin ◽  
Unique Case ◽  
Subacute Combined Degeneration ◽  
Low Serum

Coexisting deficiencies of both intrinsic factor (IF) and R binder were identified in an Algerian boy who presented with severe megaloblastic anemia, growth retardation, and neurologic dysfunction with typical features of subacute combined degeneration of the spinal cord. The anemia responded completely to cyanocobalamin and folic acid. IF was absent from gastric juice, but acid secretion and gastric mucosa were normal. R binders were absent from gastric juices as well as from serum, saliva, and polymorphonuclear leukocytes. The patient's father exhibited absence of R binder in his serum with a low serum vitamin B12 level and was asymptomatic. This unique case of simultaneous IF and R binder deficiencies suggests a genetic association between these two functionally and immunologically dissimilar, but structurally close vitamin B12-binding proteins.

Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor–vitamin B12 by cubilin

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 405-409 ◽  
Author(s):  
Mette Kristiansen ◽  
Maria Aminoff ◽  
Christian Jacobsen ◽  
Albert de la Chapelle ◽  
Ralf Krahe ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Autosomal Recessive Disorder ◽  
Site Directed Mutagenesis ◽  
Mutant Form ◽  
Wild Type ◽  
Surface Plasmon Resonance Analysis ◽  
Mammalian Expression ◽  
Iodine 125

Abstract Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder caused by the selective intestinal malabsorption of intrinsic factor (IF) and vitamin B12/cobalamin (Cbl) in complex. Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B12 receptor, cubilin. By site-directed mutagenesis, mammalian expression, and functional comparison of the purified wild-type and FM1 mutant forms of the IF–Cbl-binding cubilin region (CUB domains 5-8, amino acid 928-1386), we have investigated the functional implications of the P1297L mutation. Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the Kd for IF–Cbl binding several-fold, largely by decreasing the association rate constant. In agreement with the binding data, the wild-type protein, but not the FM1 mutant protein, potently inhibits 37°C uptake of iodine 125–IF–Cbl in cubilin-expressing epithelial cells. In conclusion, the data presented show a substantial loss in affinity of the FM1 mutant form of the IF–Cbl binding region of cubilin. This now explains the malabsorption of Cbl and Cbl-dependent anemia in MGA1 patients with the FM1 mutation.

scholarly journals Hematologic Responses and Concenrtation of Vitamin B12 in Serum and Urine following Oral Administration of Vitamin B12 without Intrinsic Factor

Blood ◽  
1954 ◽  
Vol 9 (5) ◽  
pp. 473-488 ◽  
Author(s):  
G. I. M. ROSS ◽  
D. L. MOLLIN ◽  
E. V. COX ◽  
C. C. UNGLEY
Keyword(s):  
Urinary Excretion ◽  
Vitamin B12 ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Normal Subjects ◽  
Average Amount ◽  
Hematologic Response ◽  
B12 Deficiency ◽  
Oral Doses ◽  
Lower Urinary

Abstract Vitamin B12 in doses of 500 to 3000 µg. was given by mouth or by rectum to patients with megaloblastic anemia due to B12 deficiency and to normal subjects. Its absorption was studied by following the hematologic response and/or the changes in serum and urinary B12 concentrations by microbiologic assay with Euglena gracilis var. bacillaris. After oral doses of 1000 to 3000 µg. of B12 there was a definite but variable hematologic response in the thirty-five patients. The serum B12 concentrations, measured in eighteen of these patients, increased in the first twenty-four hours after the dose. The urinary excretion of B12 increased in fifteen out of sixteen patients, but the average amount excreted was only one quarter of that excreted after intramuscular injections producing comparable hematologic responses. The lower urinary excretion after the oral doses was associated with a lower total and uncombined B12 concentration in the serum. In the majority of patients serum B12 concentrations and urinary B12 excretion reached a maximum in the first six hours after the dose. After oral doses of 3000 µg. there was a rise in serum and urinary B12 in three out of four normal subjects. After doses of 500 µg., there was an increase in the serum B12 concentrations of two normal subjects and of one out of two patients with megaloblastic anemia, but there was no change in urinary B12 excretion. After rectal doses of 1000 or 3000 µg. there was evidence of absorption of the vitamin in seven out of eight patients with pernicious anemia.

scholarly journals Combined congenital deficiencies of intrinsic factor and R binder

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 940-943
Author(s):  
J Zittoun ◽  
J Leger ◽  
J Marquet ◽  
R Carmel
Keyword(s):  
Spinal Cord ◽  
Folic Acid ◽  
Vitamin B12 ◽  
Polymorphonuclear Leukocytes ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Serum Vitamin ◽  
Unique Case ◽  
Subacute Combined Degeneration ◽  
Low Serum

Abstract Coexisting deficiencies of both intrinsic factor (IF) and R binder were identified in an Algerian boy who presented with severe megaloblastic anemia, growth retardation, and neurologic dysfunction with typical features of subacute combined degeneration of the spinal cord. The anemia responded completely to cyanocobalamin and folic acid. IF was absent from gastric juice, but acid secretion and gastric mucosa were normal. R binders were absent from gastric juices as well as from serum, saliva, and polymorphonuclear leukocytes. The patient's father exhibited absence of R binder in his serum with a low serum vitamin B12 level and was asymptomatic. This unique case of simultaneous IF and R binder deficiencies suggests a genetic association between these two functionally and immunologically dissimilar, but structurally close vitamin B12-binding proteins.

scholarly journals The Human Intrinsic Factor-Vitamin B12 Receptor,Cubilin: Molecular Characterization and Chromosomal Mapping of the Gene to 10p Within the Autosomal Recessive Megaloblastic Anemia (MGA1) Region

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3593-3600 ◽  
Author(s):  
Renata Kozyraki ◽  
Mette Kristiansen ◽  
Asli Silahtaroglu ◽  
Claus Hansen ◽  
Christian Jacobsen ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Autosomal Recessive ◽  
Megaloblastic Anemia ◽  
Intrinsic Factor ◽  
Recessive Gene ◽  
Proteolytic Processing ◽  
Chromosomal Mapping ◽  
Surface Plasmon Resonance Analysis ◽  
Amino Terminal ◽  
Resonance Analysis

Uptake of vitamin B12 (cyanocobalamin) is facilitated by the cobalamin-binder gastric intrinsic factor (IF), which recognizes a 460-kD receptor, cubilin, present in the epithelium of intestine and kidney. Surface plasmon resonance analysis of ligand-affinity-purified human cubilin demonstrated a high-affinity calcium- and cobalamin-dependent binding of IF-cobalamin. Complete cDNA cloning of the human receptor showed a 3597 amino acid peripheral membrane protein with 69% identity to rat cubilin. Amino-terminal sequencing of the receptor indicates that the cDNA sequence encodes a precursor protein undergoing proteolytic processing due to cleavage at a recognition site (Arg7-Glu8-Lys9-Arg10) for the trans-Golgi proteinase furin. Using fluorescence in situ hybridization, radiation hybrid mapping, and screening of YAC clones, the human cubilin gene was mapped between the markers D10S1661 and WI-5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia.

scholarly journals Clinico-haematological profile and etiology of bi/pancytopenia in children aged six months to eighteen years

2021 ◽  
Vol 8 (4) ◽  
pp. 732
Author(s):  
Rohan D. Venkat ◽  
Sheela A. Bharani
Keyword(s):  
Megaloblastic Anemia ◽  
Geographical Area ◽  
Cross Sectional Study ◽  
Nutritional Deficiencies ◽  
Total Leukocyte Count ◽  
Western India ◽  
Cross Sectional ◽  
Haematological Profile ◽  
Common Causes ◽  
The Common

Background: Bicytopenia/Pancytopenia is frequently found in our clinical practice having diverse etiologies, and still the optimal diagnostic approach remains undefined. Etiologies of bi/pancytopenia vary with genetic conditions, geographical area and the prevalence of infections and nutritional deficiencies in the community. The objective is to identify clinico-haematological profile and etiologies of bi/pancytopenia in children aged 6 months to 18 years from the region of western India.  Methods: A descriptive cross-sectional study was done during May 2016 to April 2018. All patients were investigated for identifying a cause of bi/ pancytopenia. Pancytopenia is defined as haemoglobin of<10 gm%, total leukocyte count<4000/mm3 with or without absolute neutrophil count of<1500/mm3, platelet count<1 lac/mm3. Bicytopenia is defined as any reduction in any two cell lineages.  Results: From 6109 hospitalized patients, 95 cases of bicytopenia and 79 of pancytopenia were evaluated. Fever, pallor, mucosal and skin bleeding were the predominant symptoms observed. Pallor was found in 90.8% cases followed by hepatomegaly in 64.8% and splenomegaly in 40.8% cases. From both bi/ pancytopenia groups, infective diseases were the common causes found in 87 (50%) cases, followed by malignancies in 28 (16%) cases and megaloblastic anemia in 22 (12.64%) cases. Aplastic anemia was found in 10 cases. Dengue fever and malaria were two common causes observed in bicytopenia group while megaloblastic anemia and acute lymphoblastic leukaemia were found in pancytopenia group.  Conclusions: Infective diseases were common causes giving rise to bi/pancytopenia. Pancytopenia is predominantly noticed in the conditions related to bone marrow production or due to infiltrative disorders.

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