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AMT
aminomethyltransferase
The AMT gene provides instructions for producing aminomethyltransferase, an enzyme vital for the breakdown of glycine within the body. The AMT gene is responsible for encoding aminomethyltransferase, a key enzyme involved in 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 gives rise to the aminomethyltransferase enzyme, a crucial component of the glycine cleavage system. This system plays a vital role in metabolising glycine, which is an amino acid that also functions as a neurotransmitter in the brain. Proper glycine breakdown is necessary for the healthy development and function of nerve cells.
Pathogenic variants in the AMT gene are associated with Nonketotic Hyperglycinaemia, an inherited metabolic disorder characterised by elevated glycine levels in the body.
What the gene does
The protein encoded by the AMT gene, aminomethyltransferase, is one of four enzymes that form the glycine cleavage system. This system operates within mitochondria, the energy-producing organelles inside cells. Its primary function is to break down glycine by cleaving it into smaller molecules.
Glycine is an amino acid, which serves as a building block for proteins, and also acts as a chemical messenger (neurotransmitter) in the brain. The efficient breakdown of excess glycine is critical for normal neurological development and function. The glycine cleavage process also generates a methyl group, which is subsequently transferred to and utilised by folate, a vitamin important for various cellular functions, including brain development.
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Chromosome location
The AMT gene is located on the long arm of chromosome 3 at position 3p21.31. This specific genomic address helps in identifying and studying the gene within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the AMT gene can alter the function of the aminomethyltransferase enzyme. Some variants may lead to a reduced or absent enzyme activity, impacting the body's ability to metabolise glycine effectively. These pathogenic variants are typically inherited in an autosomal recessive pattern.
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.1066_1067del | p.Leu356fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.1107_1108del | p.Tyr369_Ser370delinsTer | Pathogenic | ★★☆☆ | Glycine encephalopathy 2 |
c.168_171del | p.Leu57fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.224del | p.His75fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy 2 |
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 |
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, also known as Glycine Encephalopathy. This inherited metabolic condition is characterised by unusually high levels of glycine in the body, which can lead to severe neurological problems. Symptoms can vary but often include profound breathing difficulties and muscle weakness, typically presenting shortly after birth.
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 included in several NHS England national genomic testing panels. It is part of panels for conditions such as DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the AMT gene?
The AMT gene provides instructions for creating the aminomethyltransferase enzyme, which is a key component of the glycine cleavage system. This system breaks down glycine, an amino acid and neurotransmitter, essential for nerve cell function and brain development.
What condition is associated with changes in the AMT gene?
Pathogenic variants in the AMT gene are primarily associated with Nonketotic Hyperglycinaemia. This is a severe metabolic disorder characterised by an excessive accumulation of glycine in the body, leading to significant neurological issues.
How is Nonketotic Hyperglycinaemia inherited?
Nonketotic Hyperglycinaemia caused by AMT gene variants is inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
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