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AMN
amnion associated transmembrane protein
The AMN gene provides instructions for the amnionless protein, which is essential for vitamin B12 absorption in the intestines and protein reabsorption in the kidneys. The AMN gene codes for the amnionless protein, a key component of the cubam receptor complex.
AMN is located on the long (q) arm of chromosome 14, at band 14q32.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The AMN gene, or amnion associated transmembrane protein, produces a protein crucial for several physiological processes, primarily the absorption of vitamin B12 from food. Vitamin B12 is vital for DNA synthesis, energy metabolism, red blood cell formation, and the maintenance of nerve cells. The amnionless protein, along with another protein called cubilin, forms a complex known as the cubam receptor, which plays a central role in this absorption process.
Beyond its function in the intestines, the amnionless protein also contributes to the reabsorption of proteins in the kidneys, preventing their loss in urine. Understanding the AMN gene's role is important for identifying conditions linked to impaired vitamin B12 uptake and associated health issues.
What the gene does
The amnionless protein, encoded by the AMN gene, is an integral membrane protein found in cells of the intestines and kidneys. Its primary function involves forming a complex with the cubilin protein, known as the cubam receptor. This receptor is responsible for internalising the vitamin B12-intrinsic factor complex in the small intestine. In the small intestine, vitamin B12 first binds to intrinsic factor. This complex then interacts with cubilin, which is anchored to the cell membrane by the amnionless protein. The amnionless protein facilitates the transfer of this entire complex into intestinal cells, allowing vitamin B12 to be released into the bloodstream. In the kidneys, the amnionless and cubilin proteins work together to reabsorb proteins, ensuring they are not excreted in the urine. Vitamin B12 is essential for various bodily functions, including the production of red blood cells and the proper functioning of the nervous system.
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Chromosome location
The AMN gene is situated on chromosome 14 at position 14q32.32. This specific location defines its physical address within the human genome. The gene provides instructions for a protein that is 453 amino acids in length.
Protein structure
The amnionless protein consists of 453 amino acids. A key functional region, involved in its interaction with the cubilin protein, is located between amino acids 67 and 87. Additionally, a VWFC (von Willebrand Factor C) domain, important for protein-protein interactions, is found within amino acids 202-254.
Key variants
Genetic changes, known as variants, in the AMN gene can alter the structure or function of the amnionless protein. These variants can affect the protein's ability to facilitate vitamin B12 absorption or protein reabsorption. Different types of variants may have varying impacts on protein function, leading to a spectrum of clinical presentations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1173G>A | p.Trp391Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Imerslund-Grasbeck syndrome |
c.14del | p.Gly5fs | Pathogenic/Likely pathogenic | ★★☆☆ | AMN-related disorder |
g.(?_103389228)_(103394842_?)del | - | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.1161dup | p.Arg388fs | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.34C>T | p.Gln12Ter | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.411C>A | p.Cys137Ter | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.442_445dup | p.Ser149fs | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.682C>T | p.Gln228Ter | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome type 2 |
c.862C>T | p.Gln288Ter | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
c.890C>A | p.Ser297Ter | Pathogenic | ★☆☆☆ | Imerslund-Grasbeck syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the AMN gene are primarily associated with inherited disorders affecting vitamin B12 metabolism. The most notable condition linked to AMN gene variants is Imerslund-Gräsbeck syndrome. This syndrome is characterised by impaired absorption of vitamin B12, which can lead to megaloblastic anaemia and other neurological complications.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic AMN variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The AMN gene is included in several UK NHS national genomic testing panels. It is covered by panels for 'Cytopenias and congenital anaemias', 'Likely inborn error of metabolism' (R98), 'Proteinuric renal disease' (R195), 'Rare anaemia' (R92), 'Undiagnosed metabolic disorders', and 'Unexplained kidney failure in young people'. This indicates its recognised clinical significance within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the AMN gene?
The AMN gene provides instructions for the amnionless protein, which is crucial for absorbing vitamin B12 from food in the intestines and for reabsorbing proteins in the kidneys.
What health condition is associated with AMN gene variants?
Variants in the AMN gene are primarily linked to Imerslund-Gräsbeck syndrome, a condition that impairs the body's ability to absorb vitamin B12, often leading to megaloblastic anaemia.
Why is vitamin B12 important?
Vitamin B12 is essential for several vital bodily functions, including the formation of DNA, proper energy metabolism, the production of healthy red blood cells, and the maintenance of nerve cells in the brain and spinal cord.
References
- Kozyraki R, Cases O. Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders. Biochimie. 2013. PMID: 23178706
- Watkins D, Rosenblatt DS. Lessons in biology from patients with inborn errors of vitamin B12 metabolism. Biochimie. 2013. PMID: 23402785
- Namour F, Dobrovoljski G, Chery C. Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica. 2011. PMID: 21750092
- Beech CM, Liyanarachchi S, Shah NP. Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities. Orphanet journal of rare diseases. 2011. PMID: 22078000
- Fyfe JC, Madsen M, Højrup P. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood. 2004. PMID: 14576052