Human Molecular Genetics Advance Access originally published online on May 6, 2005
Human Molecular Genetics 2005 14(12):1651-1658; doi:10.1093/hmg/ddi173
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Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2
1Department of Clinical Immunology, Tissue Typing Laboratory-7631, Rigshospitalet, 2100 Copenhagen, Denmark, 2Department of Biochemistry, Fukushima Medical University School, Fukushima 960-1295, Japan and 3Department of Applied Biochemistry, Institute of Glycotechnology, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
* To whom correspondence should be addressed at: Department of Clinical Immunology, Tissue Typing Laboratory-7631, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel: +45 35457631; Fax: +45 35398766; Email: garred{at}post5.tele.dk
Received March 16, 2005; Accepted April 26, 2005
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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