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.

Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcγ Receptor Region Allows Confirmation of the Association ofFCGR3BDeletion with Rheumatoid Arthritis

“…Our data show that for the two UK samples homozygous for the FCGR3B deletion (CO092 and UKTS8802), the breakpoints all map to the same regions as previously identified [Machado et al., ; Nagelkerke et al., ]. However, two of the UK deletion alleles appear to have the same breakpoints, suggesting that these deletion alleles are identical‐by‐descent.…”

“…38, No. 4, 390-399, 2017 map to the same regions as previously identified [Machado et al, 2013;Nagelkerke et al, 2015]. However, two of the UK deletion alleles appear to have the same breakpoints, suggesting that these deletion alleles are identical-by-descent.…”

“…Three different alleles were initially found: an A to B gene conversion of about 9.1 kb (NC_000001.9:g.159806619_159815757con159888461_159897571), the reciprocal B to A gene conversion of 9.1 kb (NC_000001.9:g.159888461_159897571con159806619_159815757), and a smaller B to A gene conversion of 2.4 kb (NC_000001.9:g.159888397‐159890836con159806551_159808988). All three gene conversions occur between FCGR3A/B and FCGR2B/C in the region previously identified as a deletion breakpoint region [Machado et al., ; Mueller et al., ; Nagelkerke et al., ] (Fig. ; Table ).…”

Neonatal Alloimmune Neutropenia

“…These individuals can be immunized and produce anti-FcγRIIIb isoantibodies [27]. Furthermore, individuals can, as a result of gene duplication, have a higher expression of FcγRIIIb and subsequently be positive for more than two HNA-1 alleles [28,29,30,31]. Individuals who are HNA-2-positive mostly also have a CD177(HNA-2)-negative neutrophil subpopulation, due to lack of gene transcription in a subset of the cells [5,32,33].…”

FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma

“…The FCGR2C gene has a SNP in exon 3 (c.169 C<T, rs759550223) that influences the expression of FCGR2C on NK cell surfaces (21–23). The presence of a “C” nucleotide in this SNP leads to an open reading frame, enabling the expression of the FCGR2C receptor.…”