{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe GGTA1 gene encodes the enzyme α1,3-galactosyltransferase, which is responsible for the synthesis of Galα1-3Gal (αGal) epitopes—a set of carbohydrate markers present on the cell surfaces of most mammals. In higher primates, including humans, these epitopes are absent due to multiple critical mutations in the GGTA1 coding region, leading to the production of anti-αGal antibodies. Detailed studies have demonstrated that, despite the functional promoter in species such as the rhesus monkey, evolving point mutations and regulatory changes have rendered the gene inactive in higher primates, thereby contributing to the evolutionary loss of αGal expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of xenotransplantation, the enzymatic function of GGTA1 becomes particularly significant. Genetically engineered pigs that have been modified to knock out the GGTA1 gene show a reduction in the synthesis of these immunogenic αGal epitopes, which in turn diminishes the binding of human antibodies and improves cell survival when challenged by human immune components. This modification highlights the potential of targeting GGTA1 to minimize xenograft rejection, although some residual antibody binding remains an obstacle to complete graft acceptance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMolecular investigations into the human GGTA1 sequence have revealed that it exists as a pseudogene, marked by premature transcriptional termination that results in truncated, nonfunctional mRNAs. These aberrant transcripts lack the necessary catalytic exons to produce an active enzyme, solidifying the absence of αGal synthesis in human tissues. The identified premature stop signals and ectopic splicing events provide a mechanistic explanation for the evolutionary divergence in αGal expression between primates and other mammals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chihiro Koike, John J Fung, David A Geller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis of evolutionary loss of the alpha 1,3-galactosyltransferase gene in higher primates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110527200"}], "href": "https://doi.org/10.1074/jbc.M110527200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11773054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11773054"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Christopher Burlak, Marshall Bern, Alejandro E Brito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "N-linked glycan profiling of GGTA1/CMAH knockout pigs identifies new potential carbohydrate xenoantigens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Xenotransplantation (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/xen.12047"}], "href": "https://doi.org/10.1111/xen.12047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24033743"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24033743"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marion Lantéri, Valérie Giordanengo, Frédérique Vidal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A complete alpha1,3-galactosyltransferase gene is present in the human genome and partially transcribed."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glycobiology (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/glycob/cwf087"}], "href": "https://doi.org/10.1093/glycob/cwf087"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12499400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12499400"}]}]}]}