Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2
Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2
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DOI：
10.1093/hmg/ddi173
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发表时间：
2005-06-15
影响因子：
3.5
通讯作者：
Garred, P
中科院分区：
文献类型：
--
作者：
Hummelshoj, T;Munthe-Fog, L;Garred, P
纤维胶凝蛋白1、2和3（分别来源于FCN 1、2和3基因）是对先天免疫重要的同源可溶性模式识别分子，其包含与不同类型微生物上的糖基结合的胶原蛋白样和纤维蛋白原样结构域。Ficolin-2的血清浓度在健康个体中变化很大。因此，我们推测这是否可能是由于FCN 2基因的变异。我们对丹麦高加索人FCN 2基因的启动子区、外显子和内含子-外显子边界进行了测序。为了比较，还研究了FCN 1和FCN 3。测定血清中Ficolin-2的浓度，并通过与N-乙酰葡糖胺（GlcNAc）的结合和回收来研究FCN 2中氨基酸取代多态性的功能相关性。FCN 1和FCN 2的启动子和基因结构部分都含有多态性，但只有FCN 2的多态性导致氨基酸交换。FCN 2启动子多态性与Ficolin-2血清浓度的显著变化相关，而聚集在编码纤维蛋白原样结构域的外显子中的两个多态性分别与GlcNAc结合增加和减少相关。在FCN 3中，仅检测到外显子5中的单个移码缺失。这些结果表明，FCN基因是多态性的，特别是FCN 2窝藏功能多态性位点，调节Ficolin-2的表达和功能，这可能对先天免疫具有病理生理意义。
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.