Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.

<h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement...

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Autores principales:	Christian Gytz Ammitzbøll, Troels Rønn Kjær, Rudi Steffensen, Kristian Stengaard-Pedersen, Hans Jørgen Nielsen, Steffen Thiel, Martin Bøgsted, Jens Christian Jensenius
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8f3eb45e57f44e1dae7f89c142531344
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spelling	oai:doaj.org-article:8f3eb45e57f44e1dae7f89c1425313442021-11-18T08:07:12ZNon-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.1932-620310.1371/journal.pone.0050585https://doaj.org/article/8f3eb45e57f44e1dae7f89c1425313442012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23209787/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement system through the lectin pathway. The lectin pathway is multifaceted with activities spanning from complement activation to coagulation, autoimmunity, ischemia-reperfusion injury and embryogenesis. Our aim was to explore associations between SNPs in FCN1, encoding M-ficolin and corresponding protein concentrations, and the impact of non-synonymous SNPs on protein function.<h4>Principal findings</h4>We genotyped 26 polymorphisms in the FCN1 gene and found 8 of these to be associated with M-ficolin levels in a cohort of 346 blood donors. Four of those polymorphisms were located in the promoter region and exon 1 and were in high linkage disequilibrium (r(2)≥0.91). The most significant of those were the AA genotype of -144C>A (rs10117466), which was associated with an increase in M-ficolin concentration of 26% compared to the CC genotype. We created recombinant proteins corresponding to the five non-synonymous mutations encountered and found that the Ser268Pro (rs150625869) mutation lead to loss of M-ficolin production. This was backed up by clinical observations, indicating that an individual homozygote of Ser268Pro would be completely M-ficolin deficient. Furthermore, the Ala218Thr (rs148649884) and Asn289Ser (rs138055828) were both associated with low M-ficolin levels, and the mutations crippled the ligand-binding capability of the recombinant M-ficolin, as indicated by the low binding to Group B Streptococcus.<h4>Significance</h4>Overall, our study interlinks the genotype and phenotype relationship concerning polymorphisms in FCN1 and corresponding concentrations and biological functions of M-ficolin. The elucidations of these associations provide information for future genetic studies in the lectin pathway and complement system.Christian Gytz AmmitzbøllTroels Rønn KjærRudi SteffensenKristian Stengaard-PedersenHans Jørgen NielsenSteffen ThielMartin BøgstedJens Christian JenseniusPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e50585 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
description	<h4>Background</h4>The innate immune system encompasses various recognition molecules able to sense both exogenous and endogenous danger signals arising from pathogens or damaged host cells. One such pattern-recognition molecule is M-ficolin, which is capable of activating the complement system through the lectin pathway. The lectin pathway is multifaceted with activities spanning from complement activation to coagulation, autoimmunity, ischemia-reperfusion injury and embryogenesis. Our aim was to explore associations between SNPs in FCN1, encoding M-ficolin and corresponding protein concentrations, and the impact of non-synonymous SNPs on protein function.<h4>Principal findings</h4>We genotyped 26 polymorphisms in the FCN1 gene and found 8 of these to be associated with M-ficolin levels in a cohort of 346 blood donors. Four of those polymorphisms were located in the promoter region and exon 1 and were in high linkage disequilibrium (r(2)≥0.91). The most significant of those were the AA genotype of -144C>A (rs10117466), which was associated with an increase in M-ficolin concentration of 26% compared to the CC genotype. We created recombinant proteins corresponding to the five non-synonymous mutations encountered and found that the Ser268Pro (rs150625869) mutation lead to loss of M-ficolin production. This was backed up by clinical observations, indicating that an individual homozygote of Ser268Pro would be completely M-ficolin deficient. Furthermore, the Ala218Thr (rs148649884) and Asn289Ser (rs138055828) were both associated with low M-ficolin levels, and the mutations crippled the ligand-binding capability of the recombinant M-ficolin, as indicated by the low binding to Group B Streptococcus.<h4>Significance</h4>Overall, our study interlinks the genotype and phenotype relationship concerning polymorphisms in FCN1 and corresponding concentrations and biological functions of M-ficolin. The elucidations of these associations provide information for future genetic studies in the lectin pathway and complement system.
format	article
author	Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius
author_facet	Christian Gytz Ammitzbøll Troels Rønn Kjær Rudi Steffensen Kristian Stengaard-Pedersen Hans Jørgen Nielsen Steffen Thiel Martin Bøgsted Jens Christian Jensenius
author_sort	Christian Gytz Ammitzbøll
title	Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
title_short	Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
title_full	Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
title_fullStr	Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
title_full_unstemmed	Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.
title_sort	non-synonymous polymorphisms in the fcn1 gene determine ligand-binding ability and serum levels of m-ficolin.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/8f3eb45e57f44e1dae7f89c142531344
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Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin.

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