Alternative titles; symbols
HGNC Approved Gene Symbol: AMT
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:49,416,778-49,422,473 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Glycine encephalopathy 2 | 620398 | Autosomal recessive | 3 |
The enzyme system for cleavage of glycine (glycine cleavage system; EC 2.1.2.10), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase; GLDC, 238300), H protein (a lipoic acid-containing protein; GCSH, 238330), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase; DLD, 238331).
The T protein of the glycine cleavage system is also known as aminomethyltransferase (AMT). Nanao et al. (1994) isolated the AMT gene from a human placenta cosmid library. They identified 2 putative glucocorticoid-responsive elements and a putative thyroid hormone-responsive element.
By dot-blot analysis, Kure et al. (2001) detected expression of AMT in all tissues tested except stomach and bone marrow.
Sakata et al. (2001) reported the structure and expression of the glycine cleavage system in rat central nervous system.
Nanao et al. (1994) found that the AMT gene is about 6 kb long and contains 9 exons.
By fluorescence in situ hybridization, Nanao et al. (1994) assigned the AMT gene to chromosome 3p21.2-p21.1.
In patients with glycine encephalopathy-2 (GCE2; 620398), also known as nonketotic hyperglycinemia (NKH), Nanao et al. (1994) identified mutations in the AMT gene (238310.0001-238310.0002). Two of the patients (patient B and her affected sister) had previously been reported by Haan et al. (1986).
Toone et al. (2000) studied 14 unrelated patients with glycine encephalopathy and identified mutations in 4. In 2 patients, mutations were identified in the T protein: 1 patient was homozygous for an arg320-to-his mutation (R320H; 238310.0006), and the other patient was heterozygous for a novel gln-to-ter substitution at codon 192 (238310.0007).
Applegarth and Toone (2001) reviewed the laboratory diagnosis of glycine encephalopathy and confirmed 9 mutations in the T protein and 8 mutations in the P protein. They also reviewed the 7 cases of transient NKH known at that time.
Nanao et al. (1994) found that a patient with typical glycine encephalopathy (GCE2; 620398) was homozygous for a missense mutation in the AMT gene, a G-to-A transition leading to a gly-to-asp substitution at amino acid 269 (G269D).
In 2 sisters with atypical glycine encephalopathy (GCE2; 620398), both of whom had been reported by Haan et al. (1986), Nanao et al. (1994) found compound heterozygosity for 2 missense mutations in the T protein gene: a G-to-A transition leading to a gly-to-arg substitution at amino acid 47 (G47R) on 1 allele, and a G-to-A transition leading to an arg-to-his substitution at amino acid 320 (R320H; 238310.0006) on the other allele. Nanao et al. (1994) pointed out that gly269, which was mutant in the typically severe case they studied (see 238300.0001), is conserved in T proteins of various species, even in E. coli, whereas gly47 and arg320, which were mutant in the atypical and milder cases, are replaced by ala and leu, respectively, in E. coli. Thus, mutation occurring in more conservative amino acid residues results in more deleterious damage to the T protein and a more severe clinical phenotype.
Kure et al. (1998) reported a large Israeli-Arab kindred with glycine encephalopathy (GCE2; 620398). Enzymatic analysis demonstrated that T protein activity was deficient in the liver from 1 affected person in the family. Mutation detection revealed a missense mutation in exon 2 resulting in an amino acid substitution from histidine to arginine at position 42 (H42R). Homozygosity for the H42R mutation was seen in all affected members of the family.
In a Japanese patient with glycine encephalopathy (GCE2; 620398), Kure et al. (1998) identified compound heterozygous mutations in the AMT gene: a 1-bp deletion (183delC) in exon 1, predicted to create a truncated peptide with 94 residues, and a 955G-C transversion in exon 7, resulting in an asp276-to-his (D276H; 238310.0005) substitution. The deletion was inherited from the father and the missense mutation from the mother.
For discussion of the asp276-to-his mutation in the AMT gene that was found in compound heterozygous state in a Japanese patient with glycine encephalopathy (GCE2; 620398) by Kure et al. (1998), see 238310.0004.
For discussion of the arg320-to-his (R320H) mutation in the AMT gene that was found in compound heterozygous state in patients with glycine encephalopathy (GCE2; 620398) by Nanao et al. (1994), see 238310.0002.
In a patient with glycine encephalopathy, Toone et al. (2000) identified homozygosity for the R320H mutation in the AMT gene.
Toone et al. (2001) screened a DNA bank from 50 patients with enzymatically confirmed nonketotic hyperglycinemia and identified the R320H mutation in 7% of alleles.
In a patient with neonatal-onset glycine encephalopathy (GCE2; 620398), Toone et al. (2000) identified a C-to-T transition resulting in a gln192-to-ter (Q192X) substitution. The other mutation in this patient was not identified.
In a patient with glycine encephalopathy (GCE2; 620398), Toone et al. (2000) identified a novel splice site mutation at the -1 position of intron 7 of the AMT gene: G was converted to A. This mutation was found in 3 unrelated families and was not found in any normal controls.
In cells derived from a deceased boy, born of unrelated Serbian parents, with glycine encephalopathy (GCE2; 620398), Swanson et al. (2017) identified a homozygous c.350C-T transition (c.350C-T, NM_000481.2) in the AMT gene, resulting in a ser117-to-leu (S117L) substitution at a highly conserved residue. The mutation, which was found by direct sequencing of the AMT gene, was present only once in heterozygous state in the ExAC database. In vitro functional expression studies showed that the mutant protein was unstable and had only 9% residual enzymatic activity compared to controls. The patient was unusual because he had originally been reported as having D-glyceric aciduria (220120) caused by a homozygous frameshift mutation in the GLYCTK gene (610516.0001) (Brandt et al., 1974; Sass et al., 2010). Increased glycine in the patient had been thought to be secondary to the GLYCTK defect; however, the molecular findings confirmed that the patient had the unusual cooccurrence of 2 inborn errors of metabolism. Swanson et al. (2017) concluded that D-glyceric aciduria does not cause deficient glycine cleavage enzyme activity or nonketotic hyperglycinemia.
Applegarth, D. A., Toone, J. R. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Molec. Genet. Metab. 74: 139-146, 2001. [PubMed: 11592811] [Full Text: https://doi.org/10.1006/mgme.2001.3224]
Brandt, N. J., Brandt, S., Rasmussen, K., Schonheyder, F. Hyperglycericacidaemia with hyperglycinaemia: a new inborn error of metabolism. (Letter) Brit. Med. J. 4: 344 only, 1974. [PubMed: 4434100] [Full Text: https://doi.org/10.1136/bmj.4.5940.344-a]
Haan, E. A., Kirby, D. M., Tada, K., Hayasaka, K., Danks, D. M. Difficulties in assessing the effect of strychnine on the outcome of non-ketotic hyperglycinaemia: observations on sisters with a mild T-protein defect. Europ. J. Pediat. 145: 267-270, 1986. [PubMed: 3769993] [Full Text: https://doi.org/10.1007/BF00439398]
Hayasaka, K., Tada, K., Kikuchi, G., Winter, S., Nyhan, W. L. Nonketotic hyperglycinemia: two patients with primary defects of P-protein and T-protein, respectively, in the glycine cleavage system. Pediat. Res. 17: 967-970, 1983. [PubMed: 6336599] [Full Text: https://doi.org/10.1203/00006450-198312000-00008]
Kure, S., Kojima, K., Kudo, T., Kanno, K., Aoki, Y., Suzuki, Y., Shinka, T., Sakata, Y., Narisawa, K., Matsubara, Y. Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia. J. Hum. Genet. 46: 378-384, 2001. [PubMed: 11450847] [Full Text: https://doi.org/10.1007/s100380170057]
Kure, S., Mandel, H., Rolland, M.-O., Sakata, Y., Shinka, T., Drugan, A., Boneh, A., Tada, K., Matsubara, Y., Narisawa, K. A missense mutation (his42arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia. Hum. Genet. 102: 430-434, 1998. [PubMed: 9600239] [Full Text: https://doi.org/10.1007/s004390050716]
Kure, S., Shinka, T., Sakata, Y., Osamu, N., Takayanagi, M., Tada, K., Matsubara, Y., Narisawa, K. A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia. J. Hum. Genet. 43: 135-137, 1998. [PubMed: 9621520] [Full Text: https://doi.org/10.1007/s100380050055]
Nanao, K., Okamura-Ikeda, K., Motokawa, Y., Danks, D. M., Baumgartner, E. R., Takada, G., Hayasaka, K. Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. Hum. Genet. 93: 655-658, 1994. [PubMed: 8005589] [Full Text: https://doi.org/10.1007/BF00201565]
Nanao, K., Takada, G., Takahashi, E., Seki, N., Komatsu, Y., Okamura-Ikeda, K., Motokawa, Y., Hayasaka, K. Structure and chromosomal localization of the aminomethyltransferase gene (AMT). Genomics 19: 27-30, 1994. Note: Erratum: Genomics 20: 519 only, 1994. [PubMed: 8188235] [Full Text: https://doi.org/10.1006/geno.1994.1007]
Sakata, Y., Owada, Y., Sato, K., Kojima, K., Hisanaga, K., Shinka, T., Suzuki, Y., Aoki, Y., Satoh, J., Kondo, H., Matsubara, Y., Kure, S. Structure and expression of the glycine cleavage system in rat central nervous system. Molec. Brain Res. 94: 119-130, 2001. [PubMed: 11597772] [Full Text: https://doi.org/10.1016/s0169-328x(01)00225-x]
Sass, J. O., Fischer, K., Wang, R., Christensen, E., Scholl-Burgi, S., Chang, R., Kapelari, K., Walter, M. D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK). Hum. Mutat. 31: 1280-1285, 2010. [PubMed: 20949620] [Full Text: https://doi.org/10.1002/humu.21375]
Swanson, M. A., Garcia, S. M., Spector, E., Kronquist, K., Creadon-Swindell, G., Walter, M., Christensen, E., Van Hove, J. L. K., Sass, J. O. D-glyceric aciduria does not cause nonketotic hyperglycinemia: a historic co-occurrence. Molec. Genet. Metab. 121: 80-82, 2017. [PubMed: 28462797] [Full Text: https://doi.org/10.1016/j.ymgme.2017.04.009]
Toone, J. R., Applegarth, D. A., Coulter-Mackie, M. B., James, E. R. Biochemical and molecular investigations of patients with nonketotic hyperglycemia. Molec. Genet. Metab. 70: 116-121, 2000. [PubMed: 10873393] [Full Text: https://doi.org/10.1006/mgme.2000.3000]
Toone, J. R., Applegarth, D. A., Coulter-Mackie, M. B., James, E. R. Identification of the first reported splice site mutation (IVS7-1G-A) in the aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia. (Abstract) Hum. Mutat. 17: 76 only, 2000.
Toone, J. R., Applegarth, D. A., Coulter-Mackie, M. B., James, E. R. Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH). Molec. Genet. Metab. 72: 322-325, 2001. [PubMed: 11286506] [Full Text: https://doi.org/10.1006/mgme.2001.3158]