Alternative titles; symbols
HGNC Approved Gene Symbol: GGTA1
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38): 9:121,444,990-121,499,844 (from NCBI)
Alpha-1,3-galactosyltransferase is a Golgi membrane-bound enzyme involved in the biosynthesis of the carbohydrate chains of glycoproteins and glycolipids. Enzyme levels are developmentally regulated and differentiation dependent. The enzyme is present in most mammals but cannot be detected in man, apes, or Old World monkeys. The carbohydrate structure produced by the enzyme is immunogenic in man, and most normal, healthy individuals have a significant titer of a natural antibody against the enzyme. Aberrant expression of the enzyme in man has been implicated in autoimmune disorders and in the occurrence of certain germ cell tumors.
Joziasse et al. (1989) isolated 2 human homologs of the gene encoding the bovine enzyme. They concluded that these most likely represent a processed pseudogene (HGT-2) and the inactivated remnant of the once functional source gene (HG-10).
Joziasse et al. (1991) mapped the human GGTA1 gene to human chromosome 9 by study of human-rodent somatic cell hybrids. They mapped the processed pseudogene, GGTA1P, to human chromosome 12 by the same method. By in situ hybridization, Shaper et al. (1992) localized GGTA1 to 9q33-q34 and GGTA1P to 12q14-q15.
Joziasse et al. (1991) mapped the mouse homolog to the centromeric region of chromosome 2.
It had previously been suggested (Joziasse et al., 1991) that this enzyme is evolutionarily related to the A and B blood group transferases; the location of the gene in distal 9q in the proximity of the ABO locus lends support to this hypothesis. The ABO and GGTA1 loci evolved from an ancestral locus through duplication. Subsequently, GGTA1 gave rise to an mRNA that, after reverse transcription, was incorporated into chromosome 12 as GGTA1P. In an even later event, the ancestral human alpha-1,3-GT became inactivated, possibly through a mutation in an upstream regulatory sequence, because its transcripts are no longer detected. This situation is comparable to the loss of vitamin C synthesizing capacity (240400) or uricase enzymatic activity (191540) in the human even though sequences for the relevant genes can be identified in the human genome.
Casals et al. (2009) analyzed the human GT6 glycosyltransferase pseudogene sequences of GBGT1 (606074), IGB3 (A3GALT2P), GGTA1, GT6M5, GT6M6, and GT6M7 (GLT6D1; 613699) from an evolutionary perspective, by the study of their diversity levels in populations through the resequencing analysis of European and African individuals; the interpopulation differentiation, with genotyping data from a survey of populations covering most of human genetic diversity; and the interspecific divergence, by comparison of human and some other primate species sequences. Since pseudogenes are expected to evolve under neutrality, they should show an evolutionary pattern different than that of functional sequences, with higher levels of diversity as well as a ratio of nonsynonymous to synonymous changes close to 1. Casals et al. (2009) described some departures from these expectations, including selection for inactivation in IGB3, GGTA1, and GBGT1. These results suggest that some of these GT6 human pseudogenes may still be functional and retain some valuable unknown function in humans, in some case even at the protein level.
The presence of galactose alpha-1,3-galactose residues on the surface of pig cells is a major obstacle to successful xenotransplantation. Lai et al. (2002) reported the production of 4 live pigs in which 1 allele of the alpha-1,3-galactosyltransferase locus had been knocked out. These pigs were produced by nuclear transfer technology; clonal fetal fibroblast cell lines were used as nuclear donors for embryos reconstructed with enucleated pig oocytes.
Phelps et al. (2003) used a selection procedure based on a bacterial toxin to select for cells in which the second allele of the GGTA1 gene was knocked out in pigs carrying targeted disruption of the single allele. Sequence analysis demonstrated that knockout of the second allele was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the protein. Four healthy GGTA1 double-knockout female piglets were produced by 3 consecutive rounds of cloning. The piglets carrying a point mutation in the gene hold significant value, as they would allow production of GGTA1-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use.
Casals, F., Ferrer-Admetlla, A., Sikora, M., Ramirez-Soriano, A., Marques-Bonet, T., Despiau, S., Roubinet, Calafell, F., Bertranpetit, J., Blancher, A. Human pseudogenes of the ABO family show a complex evolutionary dynamics and loss of function. Glycobiology 19: 583-591, 2009. [PubMed: 19218399] [Full Text: https://doi.org/10.1093/glycob/cwp017]
Joziasse, D. H., Shaper, J. H., Jabs, E. W., Shaper, N. L. Characterization of an alpha-1,3-galactosyltransferase homologue on human chromosome 12 that is organized as a processed pseudogene. J. Biol. Chem. 266: 6991-6998, 1991. [PubMed: 1901859]
Joziasse, D. H., Shaper, J. H., Van den Eijnden, D. H., Van Tunen, A. J., Shaper, N. L. Bovine alpha-1,3-galactosyltransferase: isolation and characterization of a cDNA clone: identification of homologous sequences in human genomic DNA. J. Biol. Chem. 264: 14290-14297, 1989. [PubMed: 2503516]
Joziasse, D. H., Shaper, N. L., Shaper, J. H., Kozak, C. A. The gene for murine alpha-1,3-galactosyltransferase is located in the centromeric region of chromosome 2. Somat. Cell Molec. Genet. 17: 201-205, 1991. [PubMed: 1901427] [Full Text: https://doi.org/10.1007/BF01232977]
Lai, L., Kolber-Simonds, D., Park, K.-W., Cheong, H.-T., Greenstein, J. L., Im, G.-S., Samuel, M., Bonk, A., Rieke, A., Day, B. N., Murphy, C. N., Carter, D. B., Hawley, R. J., Prather, R. S. Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 295: 1089-1092, 2002. [PubMed: 11778012] [Full Text: https://doi.org/10.1126/science.1068228]
Phelps, C. J., Koike, C., Vaught, T. D., Boone, J., Wells, K. D., Chen, S.-H., Ball, S., Specht, S. M., Polejaeva, I. A., Monahan, J. A., Jobst, P. M., Sharma, S. B., and 11 others. Production of alpha-1,3-galactosyltransferase-deficient pigs. Science 299: 411-414, 2003. [PubMed: 12493821] [Full Text: https://doi.org/10.1126/science.1078942]
Shaper, N. L., Lin, S., Joziasse, D. H., Kim, D., Yang-Feng, T. L. Assignment of two human alpha-1,3-galactosyltransferase gene sequences (GGTA1 and GGTA1P) to chromosomes 9q33-q34 and 12q14-q15. Genomics 12: 613-615, 1992. Note: Erratum: Genomics 13: 493 only, 1992. [PubMed: 1559713] [Full Text: https://doi.org/10.1016/0888-7543(92)90458-5]