Alternative titles; symbols
HGNC Approved Gene Symbol: ABAT
SNOMEDCT: 237941007; ICD10CM: E72.81;
Cytogenetic location: 16p13.2 Genomic coordinates (GRCh38) : 16:8,674,617-8,784,570 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.2 | GABA-transaminase deficiency | 613163 | Autosomal recessive | 3 |
The ABAT gene encodes gamma-aminobutyrate transaminase (EC 2.6.1.19), which catalyzes the conversion of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde (Osei and Churchich, 1995).
Osei and Churchich (1995) used a probe from the pig GABAT cDNA to screen a human brain cDNA library. They identified a human GABAT cDNA, which encodes a deduced 500-amino acid protein that is over 95% similar to the pig protein. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. GABAT is present in several tissues in addition to brain and is most active in liver.
Stumpf (2023) mapped the ABAT gene to chromosome 16p13.2 based on an alignment of the ABAT sequence (GenBank BC031413) with the genomic sequence (GRCh38).
Jeremiah and Povey (1981) suggested that GABAT in liver and brain is controlled by 2 codominant alleles with a frequency in a Caucasian population of 0.56 and 0.44. A 3-banded pattern in heterozygotes suggested that GABAT is a dimeric protein. Bhattacharyya et al. (1985) gave gene frequencies for Chinese, Indians, and Malays living in Singapore and described a new allele.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
GABA-Transaminase Deficiency
In a patient with GABA-transaminase deficiency (613163) reported by Jaeken et al. (1984), Medina-Kauwe et al. (1999) identified a missense mutation in the ABAT gene (R220K; 137150.0001). The second allele in the patient remained unidentified. A second unrelated patient had a deletion in the ABAT gene (137150.0002). Both patients had severe psychomotor retardation, seizures, hypotonia, and hyperreflexia and died before age 2 years.
In a 28-month-old Japanese female with GABA-aminotransferase deficiency, Tsuji et al. (2010) identified compound heterozygous mutations in the ABAT gene (137150.0003-137150.0004).
In a child with evidence of GABA-aminotransferase deficiency, Nagappa et al. (2017) identified compound heterozygous mutations in the ABAT gene (137150.0005-137150.0006). Her parents were each heterozygous for one of the mutations, and neither variant was present in the 1000 Genomes Project database.
In an 8-year-old boy, born of consanguineous parents of Mexican descent, with GABA-aminotransferase deficiency, Koenig et al. (2017) identified a homozygous mutation in the ABAT gene (R377W; 137150.0008). Each parent was heterozygous for the mutation, which was not present in the ExAC database.
Louro et al. (2016) identified a homozygous mutation in the ABAT gene (Q296H; 137150.0009) in a Portuguese patient with GABA-transaminase deficiency. The mutation was identified by sequencing of the ABAT gene.
In 2 sibs with GABA-transaminase deficiency, Besse et al. (2015) identified a homozygous mutation in the ABAT gene (L211F; 137150.0010). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Fibroblasts with a knockdown for ABAT had reduced mtDNA copy number that was rescued by expression of wildtype ABAT but not by ABAT with a L211F, R220K (137150.0001), L478P (137150.0007), R92Q (137150.0003), or Asn67ValfsTer8 (137150.0004) mutation. To test mitochondrial reliance on the nucleotide salvage pathway, which is necessary in quiescent cells, Besse et al. (2015) grew fibroblasts from the sibs in both normal growth and regular growth media. Fibroblasts from the sibs had lower mtDNA copy number than controls when grown in normal growth media and even lower copy number when grown in low serum media. The cells were then cultured in low serum media supplemented with nucleotide pools, which rescued the mtDNA copy number. Besse et al. (2015) concluded that ABAT has an essential role in the nucleoside salvage pathway.
Besse et al. (2016) identified compound heterozygous mutations in the ABAT gene (P152S, 137150.0011 and G465R, 137150.0012) in a patient with GABA-transaminase deficiency. Fibroblasts from the patient had reduced mitochondrial membrane potential, ATP production, and oxygen consumption. ABAT with the P152S or G465R mutation, or with both mutations, was expressed in glioblastoma T98G cells with a knockdown of ABAT, which resulted in reduced mtDNA copy number, whereas expression of wildtype ABAT restored mtDNA copy number.
In a patient with GABA-transaminase deficiency (GABATD; 613163) reported by Jaeken et al. (1984), Medina-Kauwe et al. (1999) identified a 754A-G transition in the ABAT gene, resulting in an arg220-to-lys (R220K) substitution in a highly conserved residue. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose Vmax was reduced to 25% of wildtype activity. The second allele in the patient remained unidentified. Tsuji et al. (2010) stated that the R220K substitution in the patient reported by Jaeken et al. (1984) resulted from a c.659G-A transition (c.659G-A, NM_000663.3). They identified the second mutation in this patient: a c.1433T-C transition, resulting in a leu478-to-pro (L478P) substitution (137150.0007).
In a patient with GABA-transaminase deficiency (GABATD; 613163), Medina-Kauwe et al. (1999) identified a deletion of the 3-prime end of the GABAT gene.
In a 28-month-old Japanese female with GATA-transaminase deficiency (GABATD; 613163), Tsuji et al. (2010) identified compound heterozygous mutations in the ABAT gene: a c.275G-A transition (c.275G-A, NM_000663.3), resulting in an arg92-to-gln (R92Q) substitution, and an exon deletion (c.199-?_316+?; 137150.0004).
For discussion of the exon deletion (c.199-?_316+?, NM000663.3) in the ABAT gene that was found in compound heterozygous state in a patient with GABA-transaminase deficiency by Tsuji et al. (2010), see 137150.0003.
In child, born of nonconsanguineous parents, with evidence of GABA-transaminase deficiency (GABATD; 613163), Nagappa et al. (2017) identified compound heterozygous mutations in the ABAT gene: a splice site mutation (c.862-2A-G) in intron 11, and a c.1505T-C transition in exon 16, resulting in a leu502-to-pro (L502P) substitution (137150.0006). Each parent was heterozygous for one of the mutations. The mutations were found by targeted exome sequencing of a panel of 593 genes implicated in various neurologic disorders and confirmed by Sanger sequencing. Neither mutation was present in the 1000 Genomes Project database.
For discussion of the c.1505T-C transition in the ABAT gene, resulting in a leu502-to-pro (L502P) substitution, that was found in a child with evidence of GAGA-transaminase deficiency (613163) by Nagappa et al. (2017), see 137150.0005.
For discussion of the c.1433T-C transition (c.1433T-C, NM_000663.3) in the ABAT gene, resulting in a leu478-to-pro (L478P) substitution, that was found in compound heterozygous state in a patient with GABA-transaminase deficiency (613163) by Tsuji et al. (2010), see 137150.0001.
In an 8-year-old boy, born of consanguineous parents of Mexican descent, with GABA-transaminase deficiency (GABATD; 613163), Koenig et al. (2017) identified a homozygous c.1129C-T transition (c.1129C-T, NM_000663.4) in the ABAT gene, resulting in an arg377-to-trp (R377W) substitution. Each parent was heterozygous for the mutation, which was not present in the ExAC database.
In a male Portuguese infant with GABA-transaminase deficiency (GABATD; 613163), Louro et al. (2016) identified homozygosity for a c.888G-T transversion in the ABAT gene, resulting in a gln296-to-his (Q296H) substitution. The mutation was identified by sequencing of the ABAT gene.
In 2 sibs with GABA-transaminase deficiency (GABATD; 613163), Besse et al. (2015) identified homozygosity for a c.631C-T transition (c.631C-T, NM_000663.3) in the ABAT gene, resulting in a leu211-to-phe (L211F) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was not present in the ExAC database. Proton MR spectroscopy demonstrated excess GABA in the brains of both sibs.
In a patient with GABA-transaminase deficiency (GABATD; 613163), Besse et al. (2016) identified compound heterozygosity for 2 mutations in the ABAT gene, a c.454C-T transition (c.454C-T, NM_000663.4), resulting in a pro152-to-ser (P152S) substitution, and a c.1393G-C transversion, resulting in a gly465-to-arg (G465R; 137150.0012) substitution. The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. The mutations were not present in the ExAC, 1000 Genomes Project, and Exome Sequencing Project databases. CSF GABA was elevated in the patient.
For discussion of the c.1393G-C transversion (c.1393G-C, NM_000663.4) in the ABAT gene, resulting in a gly465-to-arg (G465R) substitution, that was identified in compound heterozygous state in a patient with GABA-transaminase deficiency (GABATD; 613163) by Besse et al. (2016), see 137150.0011.
Besse, A., Petersen, A. K., Hunter, J. V., Appadurai, V., Lalani, S. R., Bonnen, P. E. Personalized medicine approach confirms a milder case of ABAT deficiency. Molec. Brain 9: 93, 2016. [PubMed: 27903293] [Full Text: https://doi.org/10.1186/s13041-016-0273-8]
Besse, A., Wu, P., Bruni, F., Donti, T., Graham, B. H., Craigen, W. J., McFarland, R., Moretti, P., Lalani, S., Scott, K. L., Taylor, R. W., Bonnen, P. E. The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism. Cell Metab 21: 417-427, 2015. [PubMed: 25738457] [Full Text: https://doi.org/10.1016/j.cmet.2015.02.008]
Bhattacharyya, S. P., Saha, N., Wee, K. P. Gamma-aminobutyric acid transaminase (GABAT) polymorphism among ethnic groups in Singapore--with report of a new allele. Am. J. Hum. Genet. 37: 358-361, 1985. [PubMed: 3985010]
Jaeken, J., Casaer, P., de Cock, P., Corbeel, L., Eeckels, R., Eggermont, E., Schechter, P. J., Brucher, J.-M. Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15: 165-169, 1984. [PubMed: 6148708] [Full Text: https://doi.org/10.1055/s-2008-1052362]
Jeremiah, S., Povey, S. The biochemical genetics of human gamma-aminobutyric acid transaminase. Ann. Hum. Genet. 45: 231-236, 1981. [PubMed: 7305280] [Full Text: https://doi.org/10.1111/j.1469-1809.1981.tb00334.x]
Koenig, M. K., Hodgeman, R., Riviello, J. J. Chung, W., Bain, J., Chiriboga, C. A., Ichikawa, K., Osaka, H., Tsuji, M., Gibson, K. M., Bonnen, P. E., Pearl, P. L. Phenotype of GABA-transaminase deficiency. Neurology 88: 1919-1924, 2017. [PubMed: 28411234] [Full Text: https://doi.org/10.1212/WNL.0000000000003936]
Louro, P., Ramos, L., Robalo, C., Cancelinha, C., Dinis, A., Veiga, R., Pina, R., Rebelo, O., Pop, A., Diogo, L., Salomons, G. S., Garcia, P. Phenotyping GABA transaminase deficiency: a case description and literature review. J. Inherit. Metab. Dis. 39: 743-747, 2016. [PubMed: 27376954] [Full Text: https://doi.org/10.1007/s10545-016-9951-z]
Medina-Kauwe, L. K., Tobin, A. J., De Meirleir, L., Jaeken, J., Jakobs, C., Nyhan, W. L., Gibson, K. M. 4-aminobutyrate aminotransferase (GABA-transaminase) deficiency. J. Inherit. Metab. Dis. 22: 414-427, 1999. [PubMed: 10407778] [Full Text: https://doi.org/10.1023/a:1005500122231]
Nagappa, M., Bindu, P. S., Chiplunkar, S., Govindaraj, P., Narayanappa, G., Krishnan, A., Srinivas Bharath, M. M., Swaminathan, A., Saini, J., Arvinda, H. R., Sinha, S., Mathuranath, P. S., Taly, A. B. Hypersomnolence-hyperkinetic movement disorder in a child with compound heterozygous mutation in 4-aminobutyrate aminotransferase (ABAT) gene. Brain Dev. 39: 161-165, 2017. [PubMed: 27596361] [Full Text: https://doi.org/10.1016/j.braindev.2016.08.005]
Osei, Y. D., Churchich, J. E. Screening and sequence determination of a cDNA encoding the human brain 4-aminobutyrate aminotransferase. Gene 155: 185-187, 1995. [PubMed: 7721088] [Full Text: https://doi.org/10.1016/0378-1119(94)00858-p]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/25/2023.
Tsuji, M., Aida, N., Obata, T., Tomiyasu, M., Furuya, N., Kurosawa, K., Errami, A., Gibson, K. M., Salomons, G. s., Jakobs, C., Osaka, H. A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy. J. Inherit. Metab. Dis. 33: 85-90, 2010. [PubMed: 20052547] [Full Text: https://doi.org/10.1007/s10545-009-9022-9]