Comparison of the regulatory regions of the α1,3galactosyltransferase gene between murine and porcine species

Koike, Chihiro; Friday, Robert P.; Fung, John J.; Starzl, Thomas E.; Trucco, Massimo

doi:10.1016/s0041-1345(00)02216-8

Cited by 2 publications

(1 citation statement)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…a C connected by a 3Ј-5Ј phosphodiester bond to a G) characteristic of housekeeping genes was observed around exon 1 of the pig ␣1,3GT gene (12). It is of interest that a CpG island was not present in the mouse gene (13)(14)(15), suggesting that the upstream regulatory regions might be species-specific even though the enzyme function of the ␣1,3GT gene product was identical (15). If so, it would be conceivable that the loss of ␣Gal expression in higher primates could be due to mutation in the upstream regulatory region (16).…”

mentioning

confidence: 99%

Molecular Basis of Evolutionary Loss of the α1,3-Galactosyltransferase Gene in Higher Primates

Koike¹,

Fung²,

Geller³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Galactose-␣1,3-galactose (␣Gal) epitopes, the synthesis of which requires the enzyme product of ␣1,3-galactosyltransferase (␣1,3GT), are sugar chains on the cell surface of most mammalian species. Notable exceptions are higher primates including Old World monkeys, apes, and humans. The ␣Gal-negative species as well as mice with deletion of the ␣1,3GT gene produce abundant anti␣Gal antibodies. The evolutionary loss of ␣Gal epitopes has been attributed to point mutations in the coding region of the gene. Because no transcripts could be found in the higher primate species with Northern blot analysis, a potential alternative explanation has been loss of upstream regulation of the gene. Here, we have demonstrated that the rhesus promoter is functional. More importantly, a variety of full-length transcripts were detected with sensitive PCR-based methods in the tissues of rhesus monkeys, orangutans, and humans. Five crucial mutations were delineated in the coding region of the human and rhesus and three in the orangutan, any one of which could be responsible for inactivation of the ␣1,3GT gene. Two of the mutations were shared by all three higher primates. These findings, which elucidate the molecular basis for the evolutionary loss of ␣Gal expression, may have implications in medical research.Most mammals express the cell surface carbohydrate epitope galactose-␣1,3-galactose (␣Gal), 1 with notable exceptions that include Old World monkeys, apes, and humans (1). With the loss of the ␣Gal epitopes, the synthesis of which is dependent on enzyme product of the ␣1,3-galactosyltransferase (␣1,3GT) gene, higher primates produce anti-␣Gal antibodies (2) that are responsible for the hyperacute rejection of organs transplanted from ␣Gal-positive donors (3).In 1989, Joziasse et al. (4) reported the sequence of fulllength cDNA clone of the bovine ␣1,3GT gene and demonstrated the presence of this gene in the DNA of human cell lines. Using an 804-bp fragment derived from bovine fulllength cDNA as a probe, they also detected mRNA transcripts in bovine and marmoset (New World monkey) but not in human or African green monkey cell lines (4). The absence of ␣1,3GT mRNA has since been widely viewed as a feature of all Old World monkeys, apes, and humans (5, 6). The molecular basis for the inactivation of the ␣1,3GT gene in the ␣Gal-negative species has been attributed to a mutation(s) localized to a partial sequence of exon 9 (4, 5, 7).Stimulated by the current interest in producing transgenic pigs for clinical use as tissue and organ xenograft donors, the cDNA for the ␣1,3GT gene of the ␣Gal-positive pig was isolated (8), and the coding regions were characterized (9 -12). Further, the full genomic organization of the porcine ␣1,3GT, gene including its upstream regulatory region, was completed (12). A CpG island (i.e. a C connected by a 3Ј-5Ј phosphodiester bond to a G) characteristic of housekeeping genes was observed around exon 1 of the pig ␣1,3GT gene (12). It is of interest that a CpG island was not present in the mouse gene (13-15...

show abstract

mentioning

confidence: 99%