Genetic variation in Fcy receptors, which bind the Fc portion of IgG, may be important in disorders of host defense and systemic autoimmune diseases. Three distinct classes of Fcy receptors, FcyRI (CD64), FcyRII (CDw32), and FcyRIII (CD16), mediate a variety of biological responses including phagocytosis, antibody-dependent cellular toxicity, and platelet activation (van de Winkel and Capel 1993). Gene deletions in FCGR3B have been linked to systemic lupus erythematosus (Clark et al. 1990) and to neonatal isoimmune neutropenia in offspring of otherwise well, FCGR3B-negative mothers (Huizinga et al. 1990;Cartron et al. 1992;Fromont et al. 1992). A group of four related healthy individuals missing the FcyRIA receptor has been reported (Ceuppens et al. 1988). To date, no gene defects are described for the FcTRII class.
Genomic DNA mapping experiments were performed to analyze variation in FCGR2 gene copy number (GenBank:FCGR2A:L08107; FCGR2B:L08108; FCGR2C: L08109). Southern blots from 20 unrelated Caucasian individuals, digested with restriction enzymes Eco RI, Barn HI, or Hin dlII, revealed an expected size and intensity of FCGR2A, FCGR2B, and FCGR2C bands (Warmerdam et al. 1993; Fig. 1). However, one individual, UPN01, lacked all FCGR2C-derived bands (Fig. 1). These include the 5.5 kilobase (kb) Bam HI fragment which extends from the second extracellular domain to the intron after the second cytoplasmic domain (Fig. 1, lane 2, in comparison with lanes 3 and 4). In addition, the relative intensity of the 4.1 kb (FCGR2A/C doublet) and 6.0 kb (FCGR2B/C doublet) bands was approximately 1/2 normal (Fig. 1, lane 2), consistent with a total lack of FCGR2C-derived bands. These results were confirmed with densitometric scans of the autoradiographs (data not shown). Hin dIII and Eco RI digests from this individual further confirmed the absence of all FCGR2C-derived bands (Fig. 1, lanes 5, 8). Both parents are hemizygous and have only one copy of the FCGR2C gene (data not shown), suggesting that the proband expresses the null phenotype due to inheritance of FCGR2C-negative chromosomes from each parent. The brother has a normal complement of two FCGR2C genes, inheriting one from each parent. An additional unrelated individual was also hemizygous for FCGR2C. We describe the first example of an individual lacking all FCGR2C-derived bands. The cumulative frequency of gene deletion in our population is 7%, suggesting that deletion of an FCGR2C gene from the locus at 1@3 is not uncommon. Other investigators have reported variation in the copy number of FCGR2-1ike genes based on complex Taq I polymorphisms, but they did not identify which FCGR2 gene was involved (Jazwinska et al. 1991). Some investigators have noted mutations which render some FCGR2C alleles pseudogenes (Qiu et al. 1990;Warmerdam et al. 1993). The individual missing both FCGR2C genes in this study has no clinically apparent immune problems. The precise role of FcyRIIC and any biological consequences of the presence or absence of two functional genes warrant further study.