Human Disease Model Report: megaloblastic anemia 1

General Information

Name

megaloblastic anemia 1

FlyBase ID

FBhh0000082

Disease Ontology Term

megaloblastic anemia

Parent Disease

OMIM

IMERSLUND-GRASBECK SYNDROME 1; IGS1

Overview

This report has information on megaloblastic anemia 1 (MGA1), which exhibits autosomal recessive inheritance. The human genes implicated in this disease are AMN, which encodes the amnion associated transmembrane protein; and CUBN, which encodes the Intrinsic Factor-Cobalamin Receptor. These two proteins associate in a complex that acts as a receptor for vitamin B12 and other macromolecules; the complex is found in cells of the small intestine and the proximal tubules of the kidney. Many of the symptoms of MGA1 are due to vitamin B12 deficiency.

Work in Drosophila addresses primarily the role of the cubilin/amnionless receptor complex in a reabsorption function in the proximal tubules of the kidney; see the disease model reports for kidney disease (postulated), CUBN-related (FBhh0000550) and kidney disease (postulated), AMN-related (FBhh0000551).

[updated Jun. 2017 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: megaloblastic anemia 1

OMIM report

[IMERSLUND-GRASBECK SYNDROME 1; IGS1](https://omim.org/entry/261100)

Human gene(s) implicated

[CUBILIN; CUBN](https://omim.org/entry/602997)

Symptoms and phenotype

Features of the autosomal recessive disorder Imerslund Grasbeck syndrome (megaloblastic anemia 1) may include poor cobalamin absorption, abnormal renal tubular protein reabsorption, and urinary tract malformations. Biallelic mutations in one of two genes that encode intrinsic factor receptor components have been implicated: CUBN (encoding cubulin) and AMN (encoding amnionless) (Grasbeck, 2006, pubmed:16722557) [from GeneReviews, Disorders of Intracellular Cobalamin Metabolism, pubmed:20301503 2015.12.21]

(FlyBase Curators, 2013-)

Imerslund-Grasbeck syndrome (megaloblastic anemia 1) is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor. [From MIM:261100, 2015.12.18]

(OMIM, 2013-)

Genetics

Hereditary megaloblastic anemia-1 can be caused by recessive mutation in the genes CUBN or the AMN. The CUBN and AMN gene products form a complex that acts as a receptor for vitamin B12 and gastric intrinsic factor (GIF; MIM:609342). Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960, pubmed:13828999) in Finland; the Finnish cases were found to be due to mutations in CUBN, whereas the Norwegian cases were found to be due to mutations in AMN. [From MIM:261100, 2015.12.18]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

Cubilin (CUBN) is the intestinal receptor for the endocytosis of intrinsic factor (IF; MIM:609342)-vitamin B12 and a receptor in epithelial apoA-I/HDL (see MIM:107680) metabolism (summary by Kozyraki et al., 1998, pubmed:9572993). Cubilin colocalizes with AMN 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. Other studies indicated that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the N-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand (Fyfe, et al., 2004, pubmed:14576052). [From MIM:601623 and MIM:605799, 2015.12.21]

(OMIM, 2013-)

External links