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Alternative titles; symbols
GAMMA-AMINOBUTYRATE TRANSAMINASE; GABAT
GABA TRANSFERASE
GABA-TRANSAMINASE DEFICIENCY, INCLUDED
Gene map locus 16p13.3
TEXT
Gamma-aminobutyrate transaminase (EC 2.6.1.19) is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. 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. 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 500-amino acid protein that is over 95% similar to the pig protein. 
GABA is estimated to be present in nearly one-third of human synapses. A defect in the degradation of GABA (succinic semialdehyde dehydrogenase deficiency) results in a syndrome of mental retardation, hypotonia and ataxia (271980). Another hereditary defect of GABA catabolism ultimately associated with GABAT was discovered by Jaeken et al. (1984) in the study of 2 sibs, of consanguineous Flemish parents, who presented with severe brain disorder, leukodystrophy, and accelerated growth. The proposita had severe psychomotor retardation, hypotonia, and hyperreflexia. Her length, which at birth was at the 3rd percentile, rose to the 99th percentile by age 24 months. CSF showed high levels of free GABA, homocarnosine (a dipeptide of GABA and histidine), and beta-alanine (an alternative substrate for GABA-transaminase). Liver GABA-transaminase was deficient. Fasting plasma growth hormone levels were increased. Brain-evoked responses were suggestive of leukodystrophy. A brother, who showed a similar clinical picture, had died at 1 year of age. Postmortem showed leukodystrophy of the type seen in aminoacidopathies such as phenylketonuria. The proposita died at age 25 months (Gibson et al., 1986). Gibson et al. (1985) established autosomal recessive inheritance by finding evidence of heterozygosity in both parents and a healthy sib and homozygosity for GABA transferase deficiency in the affected Flemish child.
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.
Medina-Kauwe et al. (1999) described a second patient with GABAT deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. The second patient did not have increased linear growth as a feature of the disorder.
The International Radiation Hybrid Mapping Consortium mapped the ABAT gene to 16p13.3 (RH69040).
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
.0001 GABA-TRANSAMINASE DEFICIENCY [ABAT, ARG220LYS]
In the original case described by Jaeken et al. (1984), Medina-Kauwe et al. (1999) identified an A-to-G transition at nucleotide 754 of the ABAT gene in lymphoblast cDNA. This mutation resulted in substitution of an invariant arginine at amino acid 220 by lysine. 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.
.0002 GABA-TRANSAMINASE DEFICIENCY [ABAT, 3-PRIME DELETION ]
In a patient with GABA-transaminase deficiency, Medina-Kauwe et al. (1999) identified a deletion of the 3-prime end of the GABAT gene.
REFERENCES
- 1. 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 ID : 3985010
- 2. Gibson, K. M.; Nyhan, W. L.; Jaeken, J. :
- Inborn errors of GABA metabolism. BioEssays 4: 24-27, 1986.
PubMed ID : 3790108
- 3. Gibson, K. M.; Sweetman, L.; Nyhan, W. L.; Jansen, I.; Jaeken, J. :
- Demonstration of 4-aminobutyric acid aminotransferase deficiency in lymphocytes and lymphoblasts. J. Inherit. Metab. Dis. 8: 204-208, 1985.
PubMed ID : 3939544
- 4. 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 ID : 6148708
- 5. Jaeken, J.; Casaer, P.; De Cock, P.; et al :
- Gamma-aminobutyric acid-transaminase deficiency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15: 165-169, 1984.
PubMed ID : 6148708
- 6. Jeremiah, S.; Povey, S. :
- The biochemical genetics of human gamma-aminobutyric acid transaminase. Ann. Hum. Genet. 45: 231-236, 1981.
PubMed ID : 7305280
- 7. 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 ID : 10407778
- 8. 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 ID : 7721088
- 9. Roychoudhury, A. K.; Nei, M. :
- Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
CONTRIBUTORS
Ada Hamosh - updated : 7/15/1999
Alan F. Scott - updated : 6/21/1995
CREATION DATE
Victor A. McKusick : 6/4/1986
EDIT HISTORY
mgross : 3/17/2004
carol : 10/25/2000
joanna : 2/23/2000
alopez : 7/26/1999
terry : 7/15/1999
alopez : 8/20/1998
joanna : 5/7/1998
joanna : 5/7/1998
mimadm : 9/24/1994
warfield : 2/17/1994
supermim : 3/16/1992
carol : 2/12/1991
carol : 2/4/1991
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