Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state

被引:108
作者
Munthe-Fog, Lea [1 ,2 ]
Hummelshoj, Tina [1 ,2 ]
Ma, Ying Jie [1 ,2 ]
Hansen, Bjarke E. [1 ,2 ]
Koch, Claus [3 ]
Madsen, Hans O. [1 ,2 ]
Skjodt, Karsten [3 ]
Garred, Peter [1 ,2 ]
机构
[1] Rigshosp, Sect 7631, Dept Clin Immunol, DK-2100 Copenhagen, Denmark
[2] Univ Copenhagen, DK-2100 Copenhagen, Denmark
[3] Univ So Denmark, Dept Microbiol & Immunol, Odense, Denmark
关键词
Ficolin-3; Hakata antigen; H-ficolin; deficiency; lectin pathway; complement;
D O I
10.1016/j.molimm.2007.12.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ficolin-3 (Hakata antigen or H-ficolin) is a soluble pattern recognition molecule in the lectin complement pathway. We speculated whether common genetic variations in the FCN3 gene contribute to deficiency of Ficolin-3. The FCN3 gene was sequenced in 237 healthy Danish Caucasians. The relevance of polymorphisms was assessed with antibodies against Ficolin-3 in a novel ELISA system and by production of recombinant Ficolin-3 variants. Ficolin-3 serum profiles were analyzed by SDS-PAGE and western blotting. Ficolin-3 serum concentration varied 10-fold (median, 24 mu g/ml; range, 3-54 mu g/ml). Out of several polymorphisms one FCN3 + 1637delC causing a reading frame shift and a distortion of the C-terminal end of the molecule with an allele frequency of 0.011 was particularly interesting. In individuals heterozygous for the FCN3 + 1637delC deletion lowered Ficolin-3 concentration was observed (P = 0.025). SDS-PAGE and western blotting of serum revealed a weak band corresponding to the truncated molecule in addition to the normal Ficolin-3 pattern. Characterization of recombinant Ficolin-3 derived from FCN3 + 1637delC showed that in the homozygous situation this allelic variant would lead to Ficolin-3 deficiency. In conclusion an FCN3 + 1637delC deletion variant disrupting the possibility for pattern recognition was detected. Characterization of recombinant variant Ficolin-3 shows that homozygosity for the FCN3 + 1637delC deletion may lead to Ficolin-3 deficiency and may thus be the basis for a novel complement deficiency state. (C) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2660 / 2666
页数:7
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