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Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression

Genes & Immunity volume 16, pages 422–429 (2015)Cite this article

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Abstract

The human FCGR2/3 locus, containing five highly homologous genes encoding the major IgG receptors, shows extensive copy number variation (CNV) associated with susceptibility to autoimmune diseases. Having genotyped >4000 individuals, we show that all CNV at this locus can be explained by nonallelic homologous recombination (NAHR) of the two paralogous repeats that constitute the majority of the locus, and describe four distinct CNV regions (CNRs) with a highly variable prevalence in the population. Apart from CNV, NAHR events also created several hitherto unidentified chimeric FCGR2 genes. These include an FCGR2A/2C chimeric gene that causes a decreased expression of FcγRIIa on phagocytes, resulting in a decreased production of reactive oxygen species in response to immune complexes, compared with wild-type FCGR2A. Conversely, FCGR2C/2A chimeric genes were identified to lead to an increased expression of FCGR2C. Finally, a rare FCGR2B null-variant allele was found, in which a polymorphic stop codon of FCGR2C is introduced into one FCGR2B gene, resulting in a 50% reduction in protein expression. Our study on CNRs and the chimeric genes is essential for the correct interpretation of association studies on FCGR genes as a determinant for disease susceptibility, and may explain some as yet unidentified extreme phenotypes of immune-mediated disease.

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Acknowledgements

We thank Dr Marc Bijl, Mr Michel Tsang-a-Sjoe, Professor Dr Alexandre Voskuijl, Dr Bart Biemond, Mrs Lisa Vogelpoel and Professor Dr Martin Hibberd for help in sample collection, and Professor Dr Frank Baas for help with data analysis. This work was supported by a grant from the Landsteiner Foundation for Blood transfusion Research (LSBR 0916). CET has received a grant of the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences (TMF2012/227).

Author Contributions

SQN performed experiments, analyzed data, wrote the manuscript and designed the research; CET and JG performed experiments and analyzed data; WBB discussed data and designed the research; JWRS provided samples; BA analyzed data; TKB discussed data; MB performed experiments, analyzed and discussed data, and designed the research; and TWK discussed data, wrote the manuscript and designed the research.

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Authors and Affiliations

  1. Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    S Q Nagelkerke, J Geissler, T K van den Berg, M de Boer & T W Kuijpers

  2. Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    C E Tacke, W B Breunis, J W R Sins & T W Kuijpers

  3. Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    B Appelhof

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  1. S Q Nagelkerke
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  2. C E Tacke
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  3. W B Breunis
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  7. T K van den Berg
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  8. M de Boer
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  9. T W Kuijpers
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Correspondence to S Q Nagelkerke.

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Nagelkerke, S., Tacke, C., Breunis, W. et al. Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression. Genes Immun 16, 422–429 (2015). https://doi.org/10.1038/gene.2015.25

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