Alternative titles; symbols
HGNC Approved Gene Symbol: GOT2
Cytogenetic location: 16q21 Genomic coordinates (GRCh38): 16:58,707,131-58,734,316 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q21 | Developmental and epileptic encephalopathy 82 | 618721 | Autosomal recessive | 3 |
The GOT2 gene encodes the mitochondrial glutamate oxaloacetate transaminase, also called aspartate aminotransferase (EC 2.6.1.1), a pyridoxal 5-prime phosphate (vitamin B6)-dependent enzyme that catalyzes the reversible interconversion of oxaloacetate and glutamate into aspartate and alpha-ketoglutarate. This process is important in amino acid metabolism, the urea cycle, and intracellular NAD(H) redox homeostasis (summary by van Karnebeek et al., 2019)
By starch gel electrophoresis, Davidson et al. (1970) demonstrated polymorphism of mitochondrial glutamate oxaloacetate transaminase. In lower animals and plants, many mitochondrial enzymes show maternal inheritance, indicating that a separate mitochondrial genetic system is involved in their control. However, family studies showed that mitochondrial GOT is under the control of nuclear not mitochondrial DNA (Davidson et al., 1970). GOT2 has substrate and cofactor requirements very similar to those of cytosolic tyrosine aminotransferase (613018). Indeed, GOT2 may be responsible for the TAT activity found in mitochondria (Andersson and Pispa, 1982).
Pol et al. (1988) isolated and sequenced the cDNA of human mitochondrial aspartate aminotransferase from a human liver cDNA library. Northern blots showed a single 2.4 kb mRNA band. GOT2 mRNA was detected in kidney, placenta, stomach, and spleen, as well as in both fetal and adult liver.
Craig et al. (1978) assigned mitochondrial GOT to chromosome 6 by somatic cell hybrid studies. The presence of GOT2 was identified by an anti-GOT-antiserum. The provisional assignment to chromosome 6 was withdrawn because further study supported assignment to chromosome 16 (Francke and Weitkamp, 1979; Tolley et al., 1980). From combined somatic cell and family studies, Jeremiah et al. (1982) concluded that the gene order and map intervals are as follows: pter::PGP:0.25:16qh:0.17:GOT2:0.08:HP::qter. From 1 hybrid, 5 subclones were negative for APRT although positive for GOT2, DIA4 and PGP; APRT is assigned to 16q12-q22; DIA4 to 16q12-q21; HP to 16q22. That GOT2 is on 16q, not 16p, is supported by the fact that it is 1 of 7 genes that are on 16 in man and on chromosome 8 in the mouse; others in this group map to 16q, whereas 16p, which carries the alpha-globin cluster, is homologous to mouse 11 (Barton et al., 1986).
Pol et al. (1989) used cDNAs corresponding to human liver mitochondrial aspartate aminotransferase mRNAs as probes to confirm the location of a gene on chromosome 16, specifically at 16q21. Hybridization was also observed at 12p13.2-p13.1 and at 2 sites on chromosome 1, 1p33-p32 and 1q25-q31. These may represent pseudogenes.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Developmental and Epileptic Encephalopathy 82
In 4 patients from 3 unrelated families with developmental and epileptic encephalopathy-82 (DEE82; 618721), van Karnebeek et al. (2019) identified homozygous or compound heterozygous mutations in the GOT2 gene (138150.0001-138150.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Three mutations were missense, and 1 was an in-frame deletion of a conserved residue. All mutations occurred at highly conserved residues in the aminotransferase catalytic domain. Analysis of patient fibroblasts showed variably decreased protein levels and activity compared to controls. Patient cells and GOT2-knockout HEK293 cells had impaired de novo serine synthesis compared to controls, and the HEK293 cells also had impaired glycine synthesis; the defects could be rescued by transfection with wildtype GOT2 as well as by supplementation with pyruvate. These findings were interpreted as aiding the pathway of reoxidation of cytosolic NADH by lactate dehydrogenase (see 150000). The authors concluded that DEE82 represents a mitochondriopathy manifest as a metabolic epileptic encephalopathy.
Van Karnebeek et al. (2019) found that mice with homozygous mutations in the GOT2 found in humans with DEE82 and mice homozygous for a complete loss of Got2 died in utero, consistent with embryonic lethality. Heterozygous mice were viable and healthy. Morpholino knockdown of the got2a gene in zebrafish resulted in variable severity of developmental brain defects, small head, round or bent bodies, deformed tail, and low circulation with pericardial edema, as well as embryonic death. Mutant zebrafish also developed seizure-like episodes with EEG abnormalities in the forebrain. Treatment with pyridoxine and serine, and with pyruvate to a lesser extent, ameliorated the phenotype; pyridoxine and serine had a synergistic effect.
In an 8-year-old Romanian boy (family 1) with developmental and epileptic encephalopathy-82 (DEE82; 618721), van Karnebeek et al. (2019) identified compound heterozygous mutations in the GOT2 gene: a 3-bp in-frame deletion (c.617_619delTTC, NM_002080), resulting in the deletion of a conserved residue (Leu209del), and a c.1009C-G transversion, resulting in an arg337-to-gly (R337G; 138150.0002) substitution at a highly conserved residue. The mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent, consistent with segregation. Neither variant was found in the dbSNP (build 142), Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of more than 11,450 exomes and genomes. Both mutations occurred in the aminotransferase catalytic domain. Molecular modeling indicated that Leu209del occurs in a tri-leucine repeat that accommodates a beta-strand secondary structure and would likely adversely affect the binding of both the enzyme cofactor and substrates, whereas the R337G variant would likely destabilize the protein and impair functional protein folding. Analysis of patient fibroblasts showed decreased levels and activity of the GOT2 protein compared to controls; the defect could be rescued by wildtype GOT2. The patient had onset of seizures at age 9 months.
For discussion of the c.1009C-G transversion (c.1009C-G, NM_002080) in the GOT2 gene, resulting in an arg337-to-gly (R337G) substitution, that was found in compound heterozygous state in a patient with developmental epileptic encephalopathy-82 (DEE82; 618721) by van Karnebeek et al. (2019), see 138150.0001.
In 2 sisters, born of consanguineous Egyptian parents (family 2), with developmental and epileptic encephalopathy-82 (DEE82; 618721), van Karnebeek et al. (2019) identified a homozygous c.784C-G transversion (c.784C-G, NM_002080) in the GOT2 gene, resulting in an arg262-to-gly (R262G) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The allele frequency of the variant in gnomAD was less than 0.01%, with less than 1% among individuals of Middle Eastern origin. Molecular modeling indicated that the R262G variant occurs in the aminotransferase catalytic domain and would likely destabilize the protein and impair functional protein folding. Analysis of patient fibroblasts showed decreased levels and activity of the GOT2 protein compared to controls; the defect could be rescued by wildtype GOT2. The sibs had onset of seizures between 6 and 7 months of age.
In a 4-year-old boy, born of consanguineous Egyptian parents (family 3), with developmental and epileptic encephalopathy-82 (DEE82; 618721), van Karnebeek et al. (2019) identified a homozygous c.1097G-T transversion (c.1097G-T, NM_002080) in the GOT2 gene, resulting in a gly366-to-val (G366V) substitution at a highly conserved residue in the aminotransferase catalytic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The allele frequency of the variant in gnomAD was less than 0.01%, with less than 1% among individuals of Middle Eastern origin. Analysis of patient fibroblasts showed decreased levels and activity of the GOT2 protein compared to controls; the defect could be rescued by wildtype GOT2. The patient had onset of seizures at age 4 months.
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Francke, U., Weitkamp, L. R. Report of the committee on the genetic constitution of chromosome 6. Cytogenet. Cell Genet. 25: 32-38, 1979. [PubMed: 396126] [Full Text: https://doi.org/10.1159/000131397]
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Pol, S., Bousquet-Lemercier, B., Pave-Preux, M., Bulle, F., Passage, E., Hanoune, J., Mattei, M. G., Barouki, R. Chromosomal localization of human aspartate aminotransferase genes by in situ hybridization. Hum. Genet. 83: 159-164, 1989. [PubMed: 2777255] [Full Text: https://doi.org/10.1007/BF00286710]
Pol, S., Bousquet-Lemercier, B., Pave-Preux, M., Pawlak, A., Nalpas, B., Berthelot, P., Hanoune, J., Barouki, R. Nucleotide sequence and tissue distribution of the human mitochondrial aspartate aminotransferase mRNA. Biochem. Biophys. Res. Commun. 157: 1309-1315, 1988. [PubMed: 3207426] [Full Text: https://doi.org/10.1016/s0006-291x(88)81017-9]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Tolley, E., van Heyningen, V., Brown, R., Bobrow, M., Craig, I. W. Assignment to chromosome 16 of a gene necessary for the expression of human mitochondrial glutamate oxaloacetate transaminase (aspartate aminotransferase) (E.C. 2.6.1.1). Biochem. Genet. 18: 947-954, 1980. [PubMed: 7225087] [Full Text: https://doi.org/10.1007/BF00500127]
Toyomasu, T., Sakakibara, S., Kagamiyama, H., Matsumoto, H. Genetic polymorphism of mitochondrial glutamate-oxaloacetate transaminase in Japanese. Hum. Genet. 66: 90-91, 1984. [PubMed: 6698560] [Full Text: https://doi.org/10.1007/BF00275193]
van Karnebeek, C. D. M., Ramos, R. J., Wen, X.-Y., Tarailo-Graovac, M., Gleeson, J. G., Skrypnyk, C., Brand-Arzamendi, K., Karbassi, F., Issa, M. Y., van der Lee, R., Drogemoller, B. I., Koster, J., and 21 others. Bi-allelic GOT2 mutations cause a treatable malate-aspartate shuttle-related encephalopathy. Am. J. Hum. Genet. 105: 534-548, 2019. [PubMed: 31422819] [Full Text: https://doi.org/10.1016/j.ajhg.2019.07.015]