Alternative titles; symbols
HGNC Approved Gene Symbol: TAT
SNOMEDCT: 124287008, 4887000;
Cytogenetic location: 16q22.2 Genomic coordinates (GRCh38) : 16:71,565,660-71,577,092 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.2 | Tyrosinemia, type II | 276600 | Autosomal recessive | 3 |
Tyrosine aminotransferase (TAT; EC 2.6.1.5) is a liver-specific enzyme that converts tyrosine to p-hydroxyphenylpyruvate in a pyridoxal phosphate-dependent transamination reaction (Rettenmeier et al., 1990).
The TAT gene encodes a deduced 454-amino acid protein with a molecular mass of 50,399 daltons (Rettenmeier et al., 1990).
By analysis of cDNA and genomic clones, Rettenmeier et al. (1990) determined that the TAT gene extends over 10.9 kb and contains 12 exons giving rise to an mRNA that is 2,754 nucleotides long, excluding the poly(A) tail. The noncoding region of the 3-prime exon contains a complete Alu element.
Barton et al. (1986) assigned the tyrosine aminotransferase gene to 16q22-q24 by means of a gene clone in somatic cell hybrid analysis and in situ hybridization. Natt et al. (1986) confirmed the assignment to chromosome 16. The assignment is also supported by homology to the mouse. Muller et al. (1985) assigned the TAT locus to mouse chromosome 8 which carries 6 other loci that are on human 16: APRT (102600), CTRB (118890), HP (140100), GOT2 (138150), MT1 (156350), and MT2 (156360). All are on human 16q.
Natt et al. (1987) narrowed the assignment of TAT to 16q22.1-q22.3.
Schmid et al. (1985) identified a regulatory locus near the albino locus on mouse chromosome 7 that affects the level of Tat mRNA.
Killary and Fournier (1984) studied extinction of liver-specific tyrosine aminotransferase when rat hepatoma cells were fused with mouse fibroblasts. By microcell hybrids, they showed that mouse chromosome 11 was specifically responsible for extinction and that homologous human chromosome 17 had the same activity. The Tse1 gene (PRKAR1A; 188830) in the mouse represses gene expression in trans. To search for other Tse1-responsive genes, Lem et al. (1988) screened for expression of liver-specific mRNAs in hepatoma microcell hybrids containing mouse chromosome 11 or human chromosome 17. Whereas most liver gene activity was unaffected in such hybrids, phosphoenolpyruvate carboxykinase (261650, 261680) and tyrosine aminotransferase gene expression was coordinately repressed in these clones. Extinction of both genes was apparently mediated by a single genetic locus on human chromosome 17.
To identify the causative mutations in TAT alleles cloned from 3 patients with type II tyrosinemia (TYRSN2; 276600), Natt et al. (1992) constructed chimeric genes from normal and mutant TAT alleles and tested their ability to direct TAT activity in a transient expression assay. DNA sequence analysis of the regions identified as nonfunctional revealed 5 mutant alleles, one of which carried 2 different point mutations (613018.0001-613018.0005).
In a review of 143 patients in 106 families with tyrosinemia type II, Pena-Quintana et al. (2017) reported 36 mutations in the TAT gene, including 11 novel variants. The mutations included 3 large deletions, 21 missense and 5 nonsense amino acid substitutions, 5 frameshifts, and 2 splice variants. The most common mutation (P406L; 613018.0006) was reported in 5 patients from apparently unrelated families from the island of Gran Canaria, Spain (a population of Mediterranean ancestry). Asymptomatic parents in these families were heterozygous for the mutations, and no genotype-phenotype correlation was apparent. In addition to Gran Canaria, other areas with evidence of founder effects included northern Italy, Tunisia, Palestine, and Lebanon.
In a French patient with tyrosinemia II (TYRSN2; 276600), Natt et al. (1992) identified a CGA-to-TGA transition in the TAT gene, resulting in an arg57-to-ter (R57X) substitution. The mutation was suspected to be present in homozygous state because the patient's parents came from a small village in Lombardy.
In a Japanese patient with type II tyrosinemia (TYRSN2; 276600), Natt et al. (1992) identified compound heterozygosity for mutations in the TAT gene: a TCA-to-TGA transversion resulting in a ser223-to-ter substitution (S223X), and a splice site mutation in intron 2 (613018.0005).
In a French patient with type II tyrosinemia (TYRSN2; 276600), Natt et al. (1992) identified compound heterozygosity for a mutation in the TAT gene: a CGA-to-TGA transition resulting in an arg417-to-ter substitution (R417X) on one allele and a G362V missense mutation and a splice mutation on the other (613018.0004).
In a French patient with tyrosinemia II (TYRSN2; 276600) who had an R417X mutation on 1 allele (613018.0003) of the TAT gene, Natt et al. (1992) identified 2 point mutations on the other allele: one was a missense mutation, gly362-to-val (G362V), resulting from a GGA-to-GTA transversion; the other was a mutation in the donor splice site of intron 8 converting the second nucleotide from T to G. Identical GT-to-GG splice donor mutations in the beta-globin gene and in the factor IX gene lead to beta-0-thalassemia and severe hemophilia B, respectively.
In a Japanese patient with type II tyrosinemia (TYRSN2; 276600), Natt et al. (1992) identified compound heterozygosity for mutations in the TAT gene: an S223X substitution (613018.0002) and an A-to-G transition in intron 2, creating a new splice acceptor site 4 nucleotides 5-prime to the normal splice position. A new reading frame resulted, terminating at codon 91/92 in exon C.
In 5 probands with tyrosinemia type II (TYRSN2; 276600) from apparently unrelated families from the island of Gran Canaria, Spain (a population of Mediterranean ancestry), Pena-Quintana et al. (2017) identified a c.1217C-T transition in exon 11 of the TAT gene, resulting in a pro406-to-leu (P406L) substitution. The mutation was present in homozygosity in 4 patients and in compound heterozygosity in 1. The parents were heterozygous for the mutations. No genotype/phenotype correlation was apparent. The authors noted that P406L was the most common mutation among 36 identified in 143 patients in 106 families with the disorder.
Barton, D. E., Yang-Feng, T. L., Francke, U. The human tyrosine aminotransferase gene mapped to the long arm of chromosome 16 (region 16q22-q24) by somatic cell hybrid analysis and in situ hybridization. Hum. Genet. 72: 221-224, 1986. [PubMed: 2870017] [Full Text: https://doi.org/10.1007/BF00291881]
Killary, A. M., Fournier, R. E. K. A genetic analysis of extinction: trans-dominant loci regulate expression of liver-specific traits in hepatoma hybrid cells. Cell 38: 523-534, 1984. [PubMed: 6147198] [Full Text: https://doi.org/10.1016/0092-8674(84)90507-5]
Lem, J., Chin, A. C., Thayer, M. J., Leach, R. J., Fournier, R. E. K. Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant locus Tse-1. Proc. Nat. Acad. Sci. 85: 7302-7306, 1988. [PubMed: 2902627] [Full Text: https://doi.org/10.1073/pnas.85.19.7302]
Muller, G., Scherer, G., Zentgraf, H., Ruppert, S., Herrmann, B., Lehrach, H., Schutz, G. Isolation, characterization and chromosomal mapping of the mouse tyrosine aminotransferase gene. J. Molec. Biol. 184: 367-373, 1985. [PubMed: 2413215] [Full Text: https://doi.org/10.1016/0022-2836(85)90287-6]
Natt, E., Kao, F.-T., Rettenmeier, R., Scherer, G. Assignment of the human tyrosine aminotransferase gene to chromosome 16. Hum. Genet. 72: 225-228, 1986. [PubMed: 2870018] [Full Text: https://doi.org/10.1007/BF00291882]
Natt, E., Kida, K., Odievre, M., Di Rocco, M., Scherer, G. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc. Nat. Acad. Sci. 89: 9297-9301, 1992. [PubMed: 1357662] [Full Text: https://doi.org/10.1073/pnas.89.19.9297]
Natt, E., Westphal, E.-M., Toth-Fejel, S. E., Magenis, R. E., Buist, N. R. M., Rettenmeier, R., Scherer, G. Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1-q22.3 in a patient with tyrosinemia type II. Hum. Genet. 77: 352-358, 1987. [PubMed: 2891604] [Full Text: https://doi.org/10.1007/BF00291426]
Pena-Quintana, L., Scherer, G., Curbelo-Estevez, M. L., Jimenez-Acosta, F., Hartmann, B., La Roche, F., Meavilla-Olivas, S., Perez-Cerda, C., Garcia-Segarra, N., Giguere, Y., Huppke, P., Mitchell, G. A., Monch, E., Trump, D., Vianey-Saban, C., Trimble, E. R., Vitoria-Minana, I., Reyes-Suarez, D., Ramirez-Lorenzo, T., Tugores, A. Tyrosinemia type II: mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation. Clin. Genet. 92: 306-317, 2017. [PubMed: 28255985] [Full Text: https://doi.org/10.1111/cge.13003]
Rettenmeier, R., Natt, E., Zentgraf, H., Scherer, G. Isolation and characterization of the human tyrosine aminotransferase gene. Nucleic Acids Res. 18: 3853-3861, 1990. [PubMed: 1973834] [Full Text: https://doi.org/10.1093/nar/18.13.3853]
Schmid, W., Muller, G., Schutz, G., Gluecksohn-Waelsch, S. Deletions near the albino locus on chromosome 7 of the mouse affect the level of tyrosine aminotransferase mRNA. Proc. Nat. Acad. Sci. 82: 2866-2869, 1985. [PubMed: 2859594] [Full Text: https://doi.org/10.1073/pnas.82.9.2866]