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AMT
aminomethyltransferase
The AMT gene encodes the aminomethyltransferase enzyme, a key component of the glycine cleavage system responsible for breaking down glycine within the body's cells. The AMT gene provides instructions for creating aminomethyltransferase, an enzyme essential for the glycine cleavage system.
AMT is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The AMT gene, or aminomethyltransferase, is responsible for producing an enzyme that is integral to the glycine cleavage system. This system is a group of four enzymes working collaboratively within the mitochondria, which are the energy-producing centres of cells.
The primary role of the glycine cleavage system is to break down glycine, an amino acid that serves as a building block for proteins and a neurotransmitter in the brain. Proper glycine breakdown is necessary for the healthy development and function of nerve cells. The AMT gene's function is therefore critical for neurological health.
What the gene does
The AMT gene directs the synthesis of aminomethyltransferase, an enzyme that is a crucial part of the glycine cleavage system. This system is located in the mitochondria of cells and is responsible for metabolising glycine, an amino acid. Glycine has multiple roles, including its incorporation into proteins and its function as a chemical messenger in the brain.
The breakdown of glycine by this system is essential for maintaining appropriate levels of the amino acid, which is vital for the normal development and operation of nerve cells. When glycine is broken down, it yields a methyl group, which is then transferred to folate, a vitamin critical for various cellular functions, including brain development. Disruptions in the AMT enzyme's activity can impair this essential metabolic pathway.
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Chromosome location
The AMT gene is situated on chromosome 3 at position 3p21.31. This designation indicates that the gene is located on the short (p) arm of chromosome 3, within region 21, band 31. Understanding its genomic location helps in mapping and studying the gene's involvement in various biological processes and conditions.
Protein structure
The AMT gene encodes a protein composed of 403 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the AMT gene can alter the function of the aminomethyltransferase enzyme. These changes can range from small alterations in the DNA sequence to larger deletions or duplications. The clinical impact of a variant depends on its specific nature and its effect on the resulting protein's ability to participate in the glycine cleavage system.
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.168_171del | p.Leu57fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.224del | p.His75fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.250_251del | p.Met84fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy 2 |
c.259-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.264_265dup | p.Ile89fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy 1 |
c.317T>C | p.Ile106Thr | Pathogenic | ★★☆☆ | Glycine encephalopathy |
c.534_535dup | p.Leu179fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.602_603del | p.Lys201fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.657dup | p.Val220fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.992G>A | p.Arg331Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
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 AMT gene are primarily associated with nonketotic hyperglycinaemia. This inherited metabolic disorder is characterised by abnormally elevated levels of glycine in the body, particularly in the brain and spinal fluid. Individuals affected by this condition often experience severe neurological symptoms due to the impaired breakdown of glycine.
- Nonketotic hyperglycinaemia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic AMT 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 AMT gene is recognised within several UK NHS Genomic Medicine Service (GMS) pathways. It is listed on the DDG2P panel, the Early onset or syndromic epilepsy panel, the Foetal anomalies panel (R21), the Intellectual disability panel, the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel. Its inclusion across these panels highlights its clinical significance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AMT gene?
The AMT gene provides instructions for making the aminomethyltransferase enzyme, which is a key component of the glycine cleavage system. This system is responsible for breaking down the amino acid glycine, which is crucial for normal nerve cell development and function.
What condition is associated with variants in the AMT gene?
Variants in the AMT gene are primarily associated with nonketotic hyperglycinaemia. This condition results from the impaired breakdown of glycine, leading to its accumulation in the body, which can cause significant neurological problems.
How does the glycine cleavage system work?
The glycine cleavage system is a group of four enzymes, including aminomethyltransferase, that work together in the mitochondria. It breaks down glycine into smaller molecules, producing a methyl group that is used by folate, a vitamin important for brain development and other cellular functions.
References
- Coughlin CR 2nd, Swanson MA, Kronquist K. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genetics in medicine : official journal of the American College of Medical Genetics. 2017. PMID: 27362913
- Swanson MA, Coughlin CR Jr, Scharer GH. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Annals of neurology. 2015. PMID: 26179960
- Kikuchi G, Motokawa Y, Yoshida T. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proceedings of the Japan Academy. Series B, Physical and biological sciences. 2008. PMID: 18941301
- Kure S, Kato K, Dinopoulos A. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Human mutation. 2006. PMID: 16450403
- Okamura-Ikeda K, Hosaka H, Yoshimura M. Crystal structure of human T-protein of glycine cleavage system at 2.0 A resolution and its implication for understanding non-ketotic hyperglycinemia. Journal of molecular biology. 2005. PMID: 16051266
- Toone JR, Applegarth DA, Levy HL. Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH). Molecular genetics and metabolism. 2003. PMID: 12948742
- Adam MP, Bick S, Mirzaa GM. Nonketotic Hyperglycinemia. 1993. PMID: 20301531