On this page
AMN
amnion associated transmembrane protein
The AMN gene provides instructions for the amnionless protein, which plays a crucial role in the absorption of vitamin B12 (cobalamin) in the intestines and kidneys. The AMN gene encodes the amnionless protein, an essential 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.
Explore chromosome 14 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The AMN gene provides the genetic blueprint for a protein called amnionless, which is embedded within the cell membranes of the intestines and kidneys. This protein is indispensable for the body's ability to absorb vitamin B12, also known as cobalamin, from dietary sources. Vitamin B12 is a co-factor in critical biological processes, including the formation of DNA, metabolic pathways for energy production, and the maintenance of both red blood cells and nerve cells in the central nervous system.
Without sufficient functional amnionless protein, the body struggles to assimilate vitamin B12, potentially leading to health complications associated with deficiency.
What the gene does
The amnionless protein, encoded by the AMN gene, serves as a vital component of the cubam receptor complex. This complex, formed by amnionless binding to another protein called cubilin, is responsible for facilitating the absorption of vitamin B12 from the diet. In the small intestine, the cubilin protein within the complex can bind to vitamin B12, which is typically complexed with intrinsic factor after digestion.
The amnionless protein, anchored in the cell membrane, then assists in internalising this entire vitamin B12-intrinsic factor-cubilin complex into the intestinal cells. Once inside, vitamin B12 is released and transported into the bloodstream to fulfil its various physiological roles. Furthermore, in the kidneys, the amnionless and cubilin proteins work together to reabsorb proteins from the filtrate, preventing their loss in the urine.
Video: Genetics 101
Chromosome location
The AMN gene is situated on chromosome 14, specifically at position 14q32.32. This genomic location describes the gene's precise address on the long arm of chromosome 14.
Protein structure
The amnionless protein is composed of 453 amino acids. A key region involved in its function is the interaction site with CUBN, spanning amino acids 67-87, which is crucial for forming the cubam receptor complex. Additionally, the protein contains a VWFC domain located between amino acids 202-254, which contributes to its overall structure and function.
Key variants
Genetic variations within the AMN gene can lead to alterations in the amnionless protein, potentially affecting its ability to facilitate vitamin B12 absorption. Pathogenic variants, which are genetic changes causing disease, can disrupt the protein's structure or function. Such changes are typically inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene, one from each parent, to develop a related condition.
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 | ★★☆☆ | AMN-related disorder |
c.14del | p.Gly5fs | Pathogenic | ★★☆☆ | Imerslund-Grasbeck syndrome type 2 |
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
Pathogenic variants in the AMN gene are known to cause Imerslund-Gräsbeck syndrome. This inherited condition is characterised by a significant impairment in the body's capacity to absorb vitamin B12. A common consequence of this malabsorption is megaloblastic anaemia, a blood disorder marked by a reduced number of abnormally large red blood cells.
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, highlighting its clinical significance. It is featured in 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. Its presence on these panels indicates that genetic testing for AMN variants may be considered in the investigation of these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AMN gene?
The AMN gene provides instructions for the amnionless protein, which is critical for forming the cubam receptor complex. This complex is essential 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?
Pathogenic variants in the AMN gene are associated with Imerslund-Gräsbeck syndrome. This condition is characterised by issues with vitamin B12 absorption, often leading to megaloblastic anaemia.
How is Imerslund-Gräsbeck syndrome inherited?
Imerslund-Gräsbeck syndrome is typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic AMN variant, one from each parent, to develop the condition.
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