title: Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2.
abstract: The ficolin 1, 2 and 3 (derived from the FCN1, 2 and 3 genes, respectively) are homologous soluble pattern recognition molecules of importance for innate immunity, comprising collagen-like and fibrinogen-like domains, binding to sugar groups on different types of microorganisms. Serum concentration of Ficolin-2 varies considerably in healthy individuals. Thus, we speculated whether this could be due to variations in the FCN2 gene. We sequenced the promoter region and the exons and intron-exon boundaries of FCN2 in Danish Caucasians. For comparison, FCN1 and FCN3 were also investigated. Ficolin-2 concentrations were measured in serum and the functional relevance of amino acid substituting polymorphisms in FCN2 was investigated by binding to and recovery from N-acetylglucosamine (GlcNAc). Both FCN1 and FCN2 contained polymorphisms in the promoters and structural parts of the genes, but only polymorphisms in FCN2 resulted in amino acid exchanges. FCN2 promoter polymorphisms were associated with marked changes in the Ficolin-2 serum concentration, whereas two polymorphisms clustered in the exon encoding the fibrinogen-like domain were associated with increased and decreased GlcNAc binding, respectively. In FCN3, only a single frame-shift deletion in exon 5 was detected. These results show that the FCN genes are polymorphic and that particularly FCN2 harbors functional polymorphic sites that regulate both the expression as well as the function of Ficolin-2, which may have pathophysiological implications for innate immunity.
authors.affiliation: Department of Clinical Immunology, Tissue Typing Laboratory-7631, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Hummelshoj
authors.forename: Lea
authors.initials: L
authors.lastname: Munthe-Fog
authors.forename: Hans O
authors.initials: HO
authors.lastname: Madsen
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: Misao
authors.initials: M
authors.lastname: Matsushita
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D019943:Amino Acid Substitution; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D037102:Lectins / Q000097:blood* / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D000097604:Ficolins
chemical_list: D000117:Acetylglucosamine; D037102:Lectins; D000097604:Ficolins