title: Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression.
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.
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Nagelkerke
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: Tacke
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: Breunis
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Geissler
authors.affiliation: Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J W R
authors.initials: JW
authors.lastname: Sins
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Appelhof
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: T K
authors.initials: TK
authors.lastname: van den Berg
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: T W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000483:Alleles; D056915:DNA Copy Number Variations / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059765:Homologous Recombination; D006801:Humans; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; D050506:Mutant Chimeric Proteins; D017452:Receptors, IgG