Alternative titles; symbols
HGNC Approved Gene Symbol: MS4A2
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:60,088,259-60,098,467 (from NCBI)
The high affinity IgE receptor is responsible for initiating the allergic response. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators (such as histamine) responsible for the manifestations of allergy. The receptor is a tetrameric complex composed of an alpha chain (147140), a beta chain, and 2 disulfide-linked gamma chains (147139). It is found on the surface of mast cells and basophils. The alpha and beta subunits have not been detected in other hematopoietic cells, although the gamma chains are found in macrophages, natural killer (NK) cells, and T cells where they associate with the low affinity receptor for IgG or with the T-cell antigen receptor. The molecular cloning of subunits permitted the reconstitution of surface-expressed receptor complexes by transfection. Cotransfection of all 3 chains--alpha, beta, and gamma--was required for efficient surface expression of the rat or mouse receptor. By contrast, surface expression of the human alpha-gamma complex was achieved by cotransfecting alpha and gamma alone, suggesting that beta is not necessary. To study the expression of the beta gene, Kuster et al. (1992) isolated and characterized the gene and its cDNA. Analysis of the surface expression of transfected receptors indicated that human alpha-gamma and alpha-beta-gamma complexes are expressed with comparable efficiency.
Donnadieu et al. (2003) noted that the FCER1 tetrameric complex is expressed on mast cells and basophils, whereas the FCER1 trimeric complex lacking the beta subunit is expressed on Langerhan cells, dendritic cells, and monocytes. Thus, beta chain expression correlates with allergy mediator release, while the trimeric FCER1 form is associated with antigen presentation. The presence of the beta chain amplifies FCER1 surface expression and signaling capacity, and the beta chain acts as a chaperone for transporting the FCER1 complex to the cell surface. By RT-PCR of basophil RNA, Donnadieu et al. (2003) cloned an FCER1B splice variant that retains intron 5 and encodes a truncated protein, designated beta(T). The fourth transmembrane domain and the C-terminal tail of the full-length beta form are deleted and replaced with 16 novel amino acids in beta(T). The beta(T) variant was also present in cord blood mast cells, but not in a monocyte cell line. Immunoprecipitation and Western blot analyses showed that beta(T) was expressed as a 21-kD protein, whereas the full-length form was 28 kD.
Using RT-PCR, Cruse et al. (2010) cloned an MS4A2 splice variant lacking exon 3, which they termed MS4A2-trunc, from primary human lung mast cells and the slowly dividing mast cell line LAD-2. The variant was not expressed in the rapidly growing mast cell line HMC-1. The deduced MS4A2-trunc protein retains the cytoplasmic N and C termini of full-length MS4A2, including the noncanonical ITAM, but it lacks the first 2 transmembrane domains. Unlike full-length MS4A2, the truncated variant did not traffic to the cytoplasmic membrane, but instead to the nuclear membrane, in human mast cells.
Cruse et al. (2010) found that the MS4A2-trunc isoform was negatively regulated by SCF (KITLG; 184745) in human mast cells. Overexpression of MS4A2-trunc induced lung mast cell death and inhibited HMC-1 cell proliferation by inducing G2-phase cell-cycle arrest and apoptosis. Flow cytometric analysis demonstrated that MS4A2-trunc expression had no impact on FCER1A surface expression. Cruse et al. (2010) concluded that MS4A2 has roles, extending beyond the regulation of acute allergic responses. They proposed that induction of MS4A2 in mast cells may lead to better treatments for asthma and mastocytosis.
Cruse et al. (2013) determined that MS4A2-trunc, which they called t-FCER1B, propagated Ca(2+) signals and was critical for microtubule formation in human mast cells. Mutation analysis suggested that Ca(2+) signaling required calmodulin (CALM1; 114180) binding to t-FCER1B in the presence of Ca(2+). Silencing of t-FCER1B attenuated microtubule formation, degranulation, and IL8 (146930) production. Cruse et al. (2013) concluded that t-FCER1B plays an important role in mast cell degranulation.
Using transfection experiments, Donnadieu et al. (2003) showed that the beta(T) isoform competed with the full-length beta isoform and diminished FCER1 expression by preventing alpha chain maturation. Immunoprecipitation analysis demonstrated that beta(T) associated with immature alpha chains, but not with mature alpha chains or gamma chains. Donnadieu et al. (2003) proposed that the relative abundance of the beta and beta(T) isoforms may control the level of surface FCER1 expression and influence susceptibility to allergic disease.
Kuster et al. (1992) determined that the gene encoding the human high affinity IgE receptor beta chain spans about 10 kb and contains 7 exons. There is a single transcription initiation site preceded by a TATA box. The human beta gene appears to be present in single copy.
By linkage studies using a CA microsatellite repeat in the fifth intron of the FCER1B gene, Sandford et al. (1993) demonstrated that the gene is located on 11q13. Using in situ hybridization and pulsed-field gel electrophoresis, Szepetowski and Gaudray (1994) likewise mapped the FCER1B gene to chromosome 11q at a site centromeric from CD20 (112210) at 11q13 and in the same 550 kb fragment as TCN1 (189905), thought to be on 11q11-q12, and OSBP (167040), thought to be on 11q12-q13.
The gene for the mouse beta subunit was localized to chromosome 19 by genetic linkage studies (Hupp et al., 1989) and was thought to be a single gene. The genes for the alpha and gamma subunits are both located on human and mouse chromosome 1 (Kuster et al., 1992).
Linkage to Atopy
Sandford et al. (1993) demonstrated that the FCER1B gene is linked to clinical atopy (147050). In their linkage study of atopy, Sandford et al. (1993) used only maternally derived alleles; paternally derived alleles failed to show linkage. The known roles of the high affinity IgE receptor in antigen-induced mast cell degranulation and in the release of cytokines that enhance IgE production, taken with the location in the same region, 11q13, made the FCER1B gene a candidate for the chromosome 11 atopy locus.
Folster-Holst et al. (1998) presented evidence from linkage studies in 12 families with atopic dermatitis for linkage in close proximity to the marker D11S903. The method of analysis suggested an oligogenic mode of inheritance as well as heterogeneity in the genetic susceptibility to atopy and atopic dermatitis; only 2 of 12 families showed evidence for linkage using the oligogenic model.
Associations Pending Confirmation
Shirakawa et al. (1994) reported a significant association between atopy and substitution of a leucine for an isoleucine at position 181 of the FCER1B gene product. Hizawa et al. (1995) failed to find this leu181-to-ile substitution.
Hill and Cookson (1996) identified a novel coding polymorphism in exon 7 of the beta subunit of the high affinity receptor for IgE. An A-to-G transition changes glutamic acid-237 to glycine (147138.0001). The substitution occurs adjacent to the immunoreceptor tyrosine activation motif (ITAM). This E237G mutation was detected in 53 subjects from a general Australian population of 1004 (5.3%). E237G subjects had a significantly elevated skin test response to grass (p = 0.0004) and house dust mite (p = 0.04), RAST to grass (p = 0.0020), and bronchial reactivity to methacholine (p = 0.0009). Hill and Cookson (1996) reported that the relative risk of individuals with E237G having asthma compared to subjects without the variant was 2.3.
Traherne et al. (2003) performed association studies between FCER1B SNPs and atopy in 2 Caucasian cohorts. Independent clusters of SNPs within an 18-kb region affected prick skin tests and specific IgE responses. Interferon regulatory factor 2 (IRF2; 147576) sites were altered by significantly associated SNPs in 2 regions. Strong association to maternally derived alleles was seen in 1 panel of subjects and not in the other. Two regions of increased CpG concentration were identified in FCER1B, providing a potential substrate for epigenetic effects.
This variant, formerly titled ATOPIC ASTHMA, SUSCEPTIBILITY TO, has been reclassified as a polymorphism.
Hill and Cookson (1996) found this exon 7 E237G polymorphism in 53 of 1004 Australian subjects studied (5.3%). E237G subjects had elevated reactions to a number of common measures of atopy and bronchial hyperresponsiveness (see 147050). The investigators also found that the relative risk for E237G individuals having asthma compared to those without the allele was 2.3.
Shirakawa et al. (1996) reported that the gly237 form of the IgE Fc receptor was associated with atopic asthma (odds ratio = 3.00, chi-square = 5.10, p less than 0.03) and with elevated serum IgE levels (odds ratio = 8.56) in the Japanese population. This association was particularly noted in childhood asthma (odds ratio = 3.92, chi-square = 8.66, p less than 0.005).
Among 333 Japanese subjects, including 233 with nasal allergy and 100 controls, Nagata et al. (2001) observed a significant relationship between gly237 and elevated levels of serum total IgE and very high IgE. The findings suggested that the glu237-to-gly variant of the FCER1B gene is involved in the development of nasal allergy through the process for the production of both specific and nonspecific IgE antibodies.
Cruse, G., Beaven, M. A., Ashmole, I., Bradding, P., Gilfillan, A. M., Metcalfe, D. D. A truncated splice-variant of the Fc-epsilon-RI-beta receptor subunit is critical for microtubule formation and degranulation in mast cells. Immunity 38: 906-917, 2013. [PubMed: 23643722] [Full Text: https://doi.org/10.1016/j.immuni.2013.04.007]
Cruse, G., Kaur, D., Leyland, M., Bradding, P. A novel Fc-epsilon-RI-beta-chain truncation regulates human mast cell proliferation and survival. FASEB J. 24: 4047-4057, 2010. [PubMed: 20554927] [Full Text: https://doi.org/10.1096/fj.10-158378]
Donnadieu, E., Jouvin, M.-H., Rana, S., Moffatt, M. F., Mockford, E. H., Cookson, W. O., Kinet, J.-P. Competing functions encoded in the allergy-associated Fc-epsilon-RI-beta gene. Immunity 18: 665-674, 2003. [PubMed: 12753743] [Full Text: https://doi.org/10.1016/s1074-7613(03)00115-8]
Folster-Holst, R., Moises, H. W., Yang, L., Fritsch, W., Weissenbach, J., Christophers, E. Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families. Hum. Genet. 102: 236-239, 1998. [PubMed: 9521597] [Full Text: https://doi.org/10.1007/s004390050685]
Hill, M. R., Cookson, W. O. C. M. A new variant of the beta subunit of the high-affinity receptor for immunoglobulin E (Fc-epsilon-RI-beta E237G): associations with measures of atopy and bronchial hyper-responsiveness. Hum. Molec. Genet. 5: 959-962, 1996. [PubMed: 8817330] [Full Text: https://doi.org/10.1093/hmg/5.7.959]
Hizawa, N., Yamaguchi, E., Furuya, K., Ohnuma, N., Kodama, N., Kojima, J., Ohe, M., Kawakami, Y. Association between high serum total IgE levels and D11S97 on chromosome 11q13 in Japanese subjects. J. Med. Genet. 32: 363-369, 1995. [PubMed: 7616543] [Full Text: https://doi.org/10.1136/jmg.32.5.363]
Hupp, K., Siwarski, D., Mock, B. A., Kinet, J.-P. Gene mapping of the three subunits of the high affinity FcR for IgE to mouse chromosomes 1 and 19. J. Immun. 143: 3787-3791, 1989. [PubMed: 2531187]
Kuster, H., Zhang, L., Brini, A. T., MacGlashan, D. W. J., Kinet, J.-P. The gene and cDNA for the human high affinity immunoglobulin E receptor beta chain and expression of the complete human receptor. J. Biol. Chem. 267: 12782-12787, 1992. [PubMed: 1535625]
Nagata, H., Mutoh, H., Kumahara, K., Arimoto, Y., Tomemori, T., Sakurai, D., Arase, K., Ohno, K., Yamakoshi, T., Nakano, K., Okawa, T., Numata, T., Konno, A. Association between nasal allergy and a coding variant of the Fc-epsilon-RI-beta gene Glu237Gly in a Japanese population. Hum. Genet. 109: 262-266, 2001. [PubMed: 11702205] [Full Text: https://doi.org/10.1007/s004390100561]
Sandford, A. J., Shirakawa, T., Moffatt, M. F., Daniels, S. E., Ra, C., Faux, J. A., Young, R. P., Nakamura, Y., Lathrop, G. M., Cookson, W. O. C. M., Hopkin, J. M. Localisation of atopy and beta subunit of high-affinity IgE receptor (FCER1) on chromosome 11q. Lancet 341: 332-334, 1993. [PubMed: 8094113] [Full Text: https://doi.org/10.1016/0140-6736(93)90136-5]
Shirakawa, T., Li, A., Dubowitz, M., Dekker, J. W., Shaw, A. E., Faux, J. A., Ra, C., Cookson, W. O. C. M., Hopkin, J. M. Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor. Nature Genet. 7: 125-130, 1994. [PubMed: 7920628] [Full Text: https://doi.org/10.1038/ng0694-125]
Shirakawa, T., Mao, X.-Q., Sasaki, S., Enomoto, T., Kawai, M., Morimoto, K., Hopkin, J. Association between atopic asthma and a coding variant of Fc-epsilon-RI-beta in a Japanese population. Hum. Molec. Genet. 5: 1129-1130, 1996. Note: Erratum: Hum. Molec. Genet. 5: 2068 only, 1996. [PubMed: 8842731] [Full Text: https://doi.org/10.1093/hmg/5.8.1129]
Szepetowski, P., Gaudray, P. FCER1B, a candidate gene for atopy, is located in 11q13 between CD20 and TCN1. Genomics 19: 399-400, 1994. [PubMed: 8188278] [Full Text: https://doi.org/10.1006/geno.1994.1083]
Traherne, J. A., Hill, M. R., Hysi, P., D'Amato, M., Broxholme, J., Mott, R., Moffatt, M. F., Cookson, W. O. C. M. LD mapping of maternally and non-maternally derived alleles and atopy in Fc-epsilon-RI-beta. Hum. Molec. Genet. 12: 2577-2585, 2003. [PubMed: 12944417] [Full Text: https://doi.org/10.1093/hmg/ddg290]