title: Infection-associated FUT2 (Fucosyltransferase 2) genetic variation and impact on functionality assessed by in vivo studies.
abstract: The secretor (Se)/nonsecretor (se) histo-blood group variation depends on the action of the FUT2 enzyme and has major implications for human susceptibility to infections. To characterize the functionality of FUT2 variants, we assessed the correlation between saliva phenotypes and sequence variation at the FUT2 gene in sixty seven individuals from northern Portugal. While most non-secretor haplotypes were found to carry the 428G > A nonsense mutation in association with a 739G > A missense substitution, we have also identified a recombinant haplotype carrying the 739*A allele together with the efficient 428*G variant in individuals with the Se phenotype. This finding suggested, in contrast to previous results, that the 739*A allele encodes an efficient Se allele. To test this hypothesis we evaluated the in vivo enzyme activity of full coding expression constructs in transient transfection of CHO-K1 cells using FACS (fluorescence-activated cell sorting) analysis and expression of type 2 and type 3 chain H structures as read out. We detected FUT2 activity for the 739*A expression construct, demonstrating that the 739G > A substitution is indeed not inactivating. In accordance with the hypothesis that FUT2 is under long standing balancing selection, we estimated that the time depth of FUT2 global genetic variation is as old as 3 million years. Age estimates of specific variants suggest that the 428G > A mutation occurred at least 1.87 million years ago while the 739G > A substitution is about 816,000 years old. The 385A > T missense mutation underlying the non-secretor phenotype in East Asians appears to be more recent and is likely to have occurred about 256,000 years ago.
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Rua Dr. Roberto Frias s/n, 4200-465, Porto, Portugal.
authors.forename: Lara M
authors.initials: LM
authors.lastname: Silva
authors.forename: Ana S
authors.initials: AS
authors.lastname: Carvalho
authors.forename: Patrice
authors.initials: P
authors.lastname: Guillon
authors.forename: Susana
authors.initials: S
authors.lastname: Seixas
authors.forename: Maria
authors.initials: M
authors.lastname: Azevedo
authors.forename: Raquel
authors.initials: R
authors.lastname: Almeida
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ruvoën-Clouet
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Pendu
authors.forename: Jorge
authors.initials: J
authors.lastname: Rocha
authors.forename: Leonor
authors.initials: L
authors.lastname: David
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007239:Infections / Q000201:enzymology*; D007983:Lewis Blood Group Antigens / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D012463:Saliva / Q000201:enzymology; D014162:Transfection; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D007983:Lewis Blood Group Antigens; D050505:Mutant Proteins; D000097631:Galactoside 2-alpha-L-fucosyltransferase