*238310	GeneTests, Links
AMINOMETHYLTRANSFERASE; AMT

Alternative titles; symbols

GLYCINE CLEAVAGE SYSTEM T PROTEIN; GCST

Gene map locus 3p21.2-p21.1

TEXT

DESCRIPTION

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; 238300), H protein (a lipoic acid-containing protein; 238330), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase; 238331). Glycine encephalopathy (GCE; 605899) may be due to a defect in any one of these enzymes.

CLONING

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 found that the gene is about 6 kb long and contains 9 exons. 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.

GENE FUNCTION

Sakata et al. (2001) reported the structure and expression of the glycine cleavage system in rat central nervous system.

MAPPING

By fluorescence in situ hybridization, Nanao et al. (1994) assigned the AMT gene to 3p21.2-p21.1.

MOLECULAR GENETICS

In patients with glycine encephalopathy, Nanao et al. (1994) identified mutations in the AMT gene (238310.0001-238310.0002).

Toone et al. (2000) studied 14 unrelated patients with glycine encephalopathy and identified mutations in 4 cases. 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 glutamine-to-termination 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.

ALLELIC VARIANTS
(selected examples)

.0001 GLYCINE ENCEPHALOPATHY [AMT, GLY269ASP ]

Nanao et al. (1994) found that a patient with typical glycine encephalopathy (605899) 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).

.0002 GLYCINE ENCEPHALOPATHY [AMT, GLY47ARG ]

In 2 sisters with atypical glycine encephalopathy (605899), 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) in 1 allele, and a G-to-A transition leading to an arg-to-his substitution at amino acid 320 (R320H; 238310.0006) in 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.

.0003 GLYCINE ENCEPHALOPATHY [AMT, HIS42ARG ]

Kure et al. (1998) reported a large Israeli-Arab kindred with glycine encephalopathy (605899). 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 (his42 to arg). Homozygosity for the H42R mutation was seen in all affected members of the family.

.0004 GLYCINE ENCEPHALOPATHY [AMT, 1-BP DEL, 183C]

In a Japanese patient with glycine encephalopathy (605899), Kure et al. (1998) described a 1-bp deletion (183delC) and a missense mutation, asp276 to his (238310.0005).

.0005 GLYCINE ENCEPHALOPATHY [AMT, ASP276HIS ]

In a Japanese patient with glycine encephalopathy (605899) of neonatal onset, Kure et al. (1998) found a G-to-C substitution at position 955 in exon 7, resulting in an amino acid change from aspartate to histidine at position 276.

.0006 GLYCINE ENCEPHALOPATHY [AMT, ARG320HIS ]

See 238310.0001 and Nanao et al. (1994).

Toone et al. (2001) screened a DNA bank from 50 patients with enzymatically confirmed NKH and identified the arg320-to-his (R320H) mutation in 7% of alleles.

.0007 GLYCINE ENCEPHALOPATHY [AMT, GLN192TER ]

In a patient with neonatal-onset NKH (605899), Toone et al. (2000) identified a C-to-T transition resulting in a glutamine-to-termination codon substitution at residue 192 (Q192X). The other mutation in this patient was not identified.

.0008 GLYCINE ENCEPHALOPATHY [AMT, IVS7, G-A, -1 ]

Toone et al. (2001) reported 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.

SEE ALSO

Hayasaka et al. (1983); Toone et al. (2000)

REFERENCES

1. Applegarth, D. A.; Toone, J. R. :

Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Molec. Genet. Metab. 74: 139-146, 2001.

2. 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 ID : 6336599

3. 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 ID : 11450847

4. 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 ID : 9600239

5. 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 ID : 9621520

6. 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 ID : 8005589

7. 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.
PubMed ID : 8188235

8. 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 ID : 11597772

9. 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.

10. 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.

11. 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.

CONTRIBUTORS

Ada Hamosh - updated : 2/20/2002
Victor A. McKusick - updated : 8/10/2001
Ada Hamosh - updated : 5/2/2001
Clair A. Francomano - updated : 6/16/1998
Clair A. Francomano - updated : 5/26/1998
Beat Steinmann - updated : 1/17/1997

CREATION DATE

Victor A. McKusick : 6/3/1986

EDIT HISTORY

terry : 3/11/2002
alopez : 2/25/2002
terry : 2/20/2002
mcapotos : 8/10/2001
carol : 6/22/2001
carol : 5/3/2001
carol : 5/2/2001
carol : 4/17/2000
carol : 4/6/2000
carol : 4/4/2000
carol : 7/16/1998
carol : 6/19/1998
terry : 6/16/1998
carol : 5/30/1998
carol : 5/26/1998
dholmes : 5/21/1998
joanna : 1/17/1997
joanna : 1/17/1997
mimadm : 2/19/1994
carol : 2/7/1994
carol : 8/17/1992
supermim : 3/16/1992
supermim : 3/20/1990
carol : 12/21/1989

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