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FCER2 (Fc fragment of IgE, low affinity II, receptor for (CD23))

Written2011-06Reha Toydemir, Mohamed Salama
Department of Pathology, University of Utah, ARUP Laboratories, Salt Lake City, Utah, USA

(Note : for Links provided by Atlas : click)

Identity

Other namesCD23
CD23A
CLEC4J
FCE2
IGEBF
HGNC (Hugo) FCER2
LocusID (NCBI) 2208
Atlas_Id 44222
Location 19p13.2  [Link to chromosome band 19p13]
Location_base_pair Starts at 7753643 and ends at 7764365 bp from pter ( according to hg19-Feb_2009)  [Mapping FCER2.png]

DNA/RNA

Description The gene is localized to the short arm of chromosome 19. It contains 11 exons, and spans 13390 bps on minus strand.
Transcription Normally expressed in B-cells. Its expression has been shown on T-cells, Langerhans cells, monocytes, macrophages, platelets, and eosinophils as well.
Through alternative splicing 2 major isoforms are produced, FCER2a (CD23a) and FCER2b (CD23b), both of which are expressed on B-cells. FCER2a is constitutively expressed, whereas FCER2b is induced by several cytokines, especially by IL4. There are 3 other splice forms, whose biological significance remains to be determined.
Pseudogene N/A

Protein

Note Essential role in the regulation of IgE production as well as differentiation of B cells.
Description FCER2 is a Ca2+-dependent C-type lectin. The protein in humans contains 321 amino acids and has a molecular weight of 45 kDa. It has a single membrane-spanning domain. The extracellular domain consists of an alpha-helical coiled coil domain, a lectin head, followed by a short tail region containing an inverse RGD sequence. The coiled coil domain and the lectin head section are critical for the formation of trimers, and IgE binding, respectively. The RGD sequence is a common recognition site of integrins. Through an autocatalytic process involving matrix metalloproteases, the membrane-bound FCER2 is turned into a series of soluble fragments (sFCER2) of molecular weight ranging between 17 and 37 kDa. The soluble forms are also biologically active.
Expression FCER2 expression was first described in the thymic medullary B-lymphocytes, and subsequently, in a population of large thymic B-cells with dendritic features which were referred to as asteroid cells. FCER2 is mainly expressed on B cells. It is also expressed on T cells, Langerhans cells, monocytes, macrophages, platelets, and eosinophils. On B cells 2 isoforms are present: a constitutively active form (FCER2a) and an inducible form (FCER2b).
FCER2 expression is upregulated by its own ligand, i.e. IgE. Furthermore, upon treatment with IL4, increased FCER2 expression can be observed in several cell types including eosinophils, neutrophils, macrophages, monocytes, and T cells. In addition, EBV induces CD23 transcription through a regulatory element in intron 1 of FCER2a.
FCER2 expression levels are differentially higher (70%) in mediastinal diffuse large B-cell lymphoma (med-DLBCL) and lower in nonmediastinal nodal DLBCL (15%) and extranodal DLBCL (9%).
Localisation Although FCER2 expression is mainly localized to the surface of B-lymphocytes, it is widely distributed on the surface of various other cells including follicular dendritic cells (FDC), and even airway smooth muscle cells.
Function FCER2 is the low-affinity immunoglobin E receptor. It mediates various biological functions. Mainly, it is involved in the down regulation of IgE production by B cells. However, because of its ability to associate with various ligands, its effects on IgE regulation might be stimulatory as well. In fact, FCER2 has been implicated in a variety of cellular functions ranging from cellular adhesion, antigen presentation, growth and differentiation of B and T cells, rescue from apoptosis, release of cytotoxic mediators, and regulation of IgE synthesis.
FCER2 displays susceptibility to proteolytic cleavage which produces a soluble form of FCER2. As the soluble FCER2 does not have the ability to bind to the cell surface, this results in disruption of the feedback inhibition mechanism and increase of IgE production. As a result, soluble FCER2 has mitogenic properties. Furthermore, the proteolytic cleavage of FCER2 is probably the basis of various allergic reactions.
These observations have been supported by cellular and animal models. Antibodies directed against the soluble FCER2 have been shown to inhibit the synthesis of IgE, while cross linking of membrane-bound FCER2 inhibits B-cell growth and differentiation. Furthermore, FCER2-deficient mice produce higher levels of IgE, whereas mice overexpressing membrane-bound FCER2 exhibit weaker IgE responses.
Lumiliximab is an anti-CD23 antibody that is proposed in the therapy of chronic lymphocytic leukemia (CLL). Lumiliximab binds to cell surface membrane FCER, and induce apoptosis. Although previous reports indicated activation of the caspase cascade, the exact mechanism for apoptosis remains to be elucidated.
Homology At this time a paralogous gene is not known in humans. It does not show similarity to FCER1, the other member of the immunoglobin E receptor family.
Orthologues have been shown in mouse, rat and cow, with up to 58% homology at the protein level. However, some of the domains required for the proper function of human FCER2 is absent in orthologues. For example, the murine FCER2 does not have the RGD motif nor does it retain the IgE-binding affinity.

Mutations

Germinal An arginine to tryptophane substitution of amino acid 62 (p.R62W) have been suggested to affect the receptor function and the mitogenic role of the protein. This suggestion was based on in vitro studies which showed the mutant protein was resistant to proteolytic cleavage following treatment with a broad range of proteases.
Somatic N/A

Implicated in

Note
Entity Mediastinal diffuse large B-cell lymphoma (Med-DLBCL)
Disease Med-DLBCL is a subtype of DLBCL that arise in the mediastinum from putative thymic B-cell origin. Its clinical, immunophenotypic, and genotypic features are distinctive. However, it has significant morphologic and immunophenotypic similarities with classical Hodgkin lymphoma (CHL) involving mediastinum. Since the prognosis and the first line of therapy for these conditions differ significantly, previous studies highlighted the usefulness of CD23 expression in the differential diagnosis of these conditions. Up to 85% of med-DLBCL patients are positive for FCER2, whereas only 10% of CHL patients show a weak FCER2 staining, suggesting that FCER2 might be helpful to distinguish between med-DLBCL and CHL.
Cytogenetics N/A
  
Entity Chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL)
Disease CD23 positivity is noted in most cases of CLL/SLL and is used to differentiate CLL/SLL from mantle cell lymphoma that shares the CD5+ B-cell phenotype. The lack of CD23 in mantle cell lymphoma along with the dim expression of CD20 and light chain in CLL often help in this important distinction given the difference in prognosis and therapeutic options. However, some case of CLL/SLL may have an atypical phenotype including the lack of CD23 expression; posing diagnostic difficulty.
Cytogenetics N/A
  
Entity Nodal marginal zone B-cell lymphoma (NMZL)
Disease NMZL is a rare form of non-Hodgkin lymphoma with primary presentation in the lymph node in the absence of clinical evidence of prior or concurrent involvement of extranodal sites or spleen. In a comprehensive study, FCER2 was found to highlight neoplastic cells in a case in which the staining was diffuse but weakly positive. Furthermore, the FCER2 staining highlighted residual and disrupted follicular dendritic cell (FDC) meshwork in 40% of the NMZL cases that were also highlighted by CD21 staining.
Cytogenetics N/A
  
Entity Follicular lymphoma (FL)
Disease CD23 positivity by immunohistochemical analysis has been recently linked to a specific anatomic site in FL. Thorns et al. (2007) found that FLs in inguinal lymph nodes were more commonly CD23+ compared with FL from other anatomic sites. Katzenberger et al. (2009) demonstrated a high proportion of CD23+ cases in FLs with a diffuse growth pattern and a specific chromosomal alteration (deletion 1p36). CD23 expression in FL was most recenlty reported to be associated with favorable outcome by Olteano et al. (2011) who also reported that CD23 positivity was more common in inguinal lymph nodes and in low-grade cases. They postulated that CD23 expression is at least partially modulated by the tissue- and/or host-specific factors (such as anatomic site or lower histologic grade) and suggested CD23 expression may be a surrogate for a certain host-specific (possibly, immune) environment that is associated with a more indolent disease course and, thus, with a favorable outcome.
Cytogenetics N/A
  

Bibliography

Functional and clinical consequences of Fc receptor polymorphic and copy number variants.
Bournazos S, Woof JM, Hart SP, Dransfield I.
Clin Exp Immunol. 2009 Aug;157(2):244-54. (REVIEW)
PMID 19604264
 
CD23 expression in mediastinal large B-cell lymphomas.
Calaminici M, Piper K, Lee AM, Norton AJ.
Histopathology. 2004 Dec;45(6):619-24.
PMID 15569053
 
Phenotype and topography of human thymic B cells. An immunohistologic study.
Fend F, Nachbaur D, Oberwasserlechner F, Kreczy A, Huber H, Muller-Hermelink HK.
Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(6):381-8.
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Isaacson PG, Norton AJ, Addis BJ.
Lancet. 1987 Dec 26;2(8574):1488-91.
PMID 2447458
 
A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36.
Katzenberger T, Kalla J, Leich E, Stocklein H, Hartmann E, Barnickel S, Wessendorf S, Ott MM, Muller-Hermelink HK, Rosenwald A, Ott G.
Blood. 2009 Jan 29;113(5):1053-61. Epub 2008 Oct 31.
PMID 18978208
 
Regulation of the human IgE receptor (Fc epsilon RII/CD23) by EBV. Localization of an intron EBV-responsive enhancer and characterization of its cognate GC-box binding factors.
Lacy J, Roth G, Shieh B.
J Immunol. 1994 Dec 15;153(12):5537-48.
PMID 7989755
 
Polymorphism R62W results in resistance of CD23 to enzymatic cleavage in cultured cells.
Meng JF, McFall C, Rosenwasser LJ.
Genes Immun. 2007 Apr;8(3):215-23. Epub 2007 Feb 15.
PMID 17301828
 
CD23 expression in follicular lymphoma: clinicopathologic correlations.
Olteanu H, Fenske TS, Harrington AM, Szabo A, He P, Kroft SH.
Am J Clin Pathol. 2011 Jan;135(1):46-53.
PMID 21173123
 
Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23+ lymphoma cell lines.
Pathan NI, Chu P, Hariharan K, Cheney C, Molina A, Byrd J.
Blood. 2008 Feb 1;111(3):1594-602. Epub 2007 Nov 21.
PMID 18032710
 
Murine models of inflammation: role of CD23.
Riffo-Vasquez Y, Pitchford S, Spina D.
Allergy. 2000;55 Suppl 61:21-6. (REVIEW)
PMID 10919501
 
Immunoarchitectural patterns in nodal marginal zone B-cell lymphoma: a study of 51 cases.
Salama ME, Lossos IS, Warnke RA, Natkunam Y.
Am J Clin Pathol. 2009 Jul;132(1):39-49.
PMID 19864232
 
The value of CD23 expression as an additional marker in distinguishing mediastinal (thymic) large B-cell lymphoma from Hodgkin lymphoma.
Salama ME, Rajan Mariappan M, Inamdar K, Tripp SR, Perkins SL.
Int J Surg Pathol. 2010 Apr;18(2):121-8. Epub 2009 Feb 17.
PMID 19223373
 
FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma.
Tantisira KG, Silverman ES, Mariani TJ, Xu J, Richter BG, Klanderman BJ, Litonjua AA, Lazarus R, Rosenwasser LJ, Fuhlbrigge AL, Weiss ST.
J Allergy Clin Immunol. 2007 Dec;120(6):1285-91. Epub 2007 Nov 5.
PMID 17980418
 
Significant high expression of CD23 in follicular lymphoma of the inguinal region.
Thorns C, Kalies K, Fischer U, Hofig K, Krokowski M, Feller AC, Merz H, Bernd HW.
Histopathology. 2007 May;50(6):716-9.
PMID 17493235
 
The role of CD23 in allergic disease.
Tsicopoulos A, Joseph M.
Clin Exp Allergy. 2000 May;30(5):602-5. (REVIEW)
PMID 10792350
 

Citation

This paper should be referenced as such :
Toydemir, R ; Salama, M
FCER2 (Fc fragment of IgE, low affinity II, receptor for (CD23))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1005-1007.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FCER2ID44222ch19p13.html


External links

Nomenclature
HGNC (Hugo)FCER2   3612
Cards
AtlasFCER2ID44222ch19p13
Entrez_Gene (NCBI)FCER2  2208  Fc fragment of IgE receptor II
AliasesBLAST-2; CD23; CD23A; CLEC4J; 
FCE2; IGEBF
GeneCards (Weizmann)FCER2
Ensembl hg19 (Hinxton)ENSG00000104921 [Gene_View]  chr19:7753643-7764365 [Contig_View]  FCER2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000104921 [Gene_View]  chr19:7753643-7764365 [Contig_View]  FCER2 [Vega]
ICGC DataPortalENSG00000104921
TCGA cBioPortalFCER2
AceView (NCBI)FCER2
Genatlas (Paris)FCER2
WikiGenes2208
SOURCE (Princeton)FCER2
Genomic and cartography
GoldenPath hg19 (UCSC)FCER2  -     chr19:7753643-7764365 -  19p13.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)FCER2  -     19p13.3   [Description]    (hg38-Dec_2013)
EnsemblFCER2 - 19p13.3 [CytoView hg19]  FCER2 - 19p13.3 [CytoView hg38]
Mapping of homologs : NCBIFCER2 [Mapview hg19]  FCER2 [Mapview hg38]
OMIM151445   
Gene and transcription
Genbank (Entrez)AK223207 AK310071 AK310707 BC014108 BC062591
RefSeq transcript (Entrez)NM_001207019 NM_001220500 NM_002002
RefSeq genomic (Entrez)NC_000019 NC_018930 NG_029554 NT_011295 NW_004929413
Consensus coding sequences : CCDS (NCBI)FCER2
Cluster EST : UnigeneHs.465778 [ NCBI ]
CGAP (NCI)Hs.465778
Alternative Splicing GalleryENSG00000104921
Gene ExpressionFCER2 [ NCBI-GEO ]   FCER2 [ EBI - ARRAY_EXPRESS ]   FCER2 [ SEEK ]   FCER2 [ MEM ]
Gene Expression Viewer (FireBrowse)FCER2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2208
GTEX Portal (Tissue expression)FCER2
Protein : pattern, domain, 3D structure
UniProt/SwissProtP06734 (Uniprot)
NextProtP06734  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP06734
Splice isoforms : SwissVarP06734 (Swissvar)
PhosPhoSitePlusP06734
Domaine pattern : Prosite (Expaxy)C_TYPE_LECTIN_1 (PS00615)    C_TYPE_LECTIN_2 (PS50041)   
Domains : Interpro (EBI)C-type_lectin    C-type_lectin-like    C-type_lectin_CS    C-type_lectin_fold   
Domain families : Pfam (Sanger)Lectin_C (PF00059)   
Domain families : Pfam (NCBI)pfam00059   
Domain families : Smart (EMBL)CLECT (SM00034)  
DMDM Disease mutations2208
Blocks (Seattle)FCER2
PDB (SRS)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
PDB (PDBSum)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
PDB (IMB)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
PDB (RSDB)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
Structural Biology KnowledgeBase1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
SCOP (Structural Classification of Proteins)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
CATH (Classification of proteins structures)1HLI    1KJE    1T8C    1T8D    2H2R    2H2T    4EZM    4G96    4G9A    4GI0    4GJ0    4GJX    4GK1    4GKO    4J6J    4J6K    4J6L    4J6M    4J6N    4J6P    4J6Q    4KI1   
SuperfamilyP06734
Human Protein AtlasENSG00000104921
Peptide AtlasP06734
HPRD01049
IPIIPI00027491   IPI00217263   
Protein Interaction databases
DIP (DOE-UCLA)P06734
IntAct (EBI)P06734
FunCoupENSG00000104921
BioGRIDFCER2
STRING (EMBL)FCER2
ZODIACFCER2
Ontologies - Pathways
QuickGOP06734
Ontology : AmiGOpositive regulation of humoral immune response mediated by circulating immunoglobulin  integrin binding  protein binding  plasma membrane  integral component of plasma membrane  Notch signaling pathway  external side of plasma membrane  IgE binding  carbohydrate binding  metal ion binding  positive regulation of nitric-oxide synthase activity  positive regulation of killing of cells of other organism  positive regulation of nitric-oxide synthase biosynthetic process  extracellular exosome  
Ontology : EGO-EBIpositive regulation of humoral immune response mediated by circulating immunoglobulin  integrin binding  protein binding  plasma membrane  integral component of plasma membrane  Notch signaling pathway  external side of plasma membrane  IgE binding  carbohydrate binding  metal ion binding  positive regulation of nitric-oxide synthase activity  positive regulation of killing of cells of other organism  positive regulation of nitric-oxide synthase biosynthetic process  extracellular exosome  
Pathways : KEGGHematopoietic cell lineage    Epstein-Barr virus infection   
REACTOMEP06734 [protein]
REACTOME PathwaysR-HSA-2197563 NOTCH2 intracellular domain regulates transcription [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkFCER2
Wikipedia pathwaysFCER2
Orthology - Evolution
OrthoDB2208
GeneTree (enSembl)ENSG00000104921
Phylogenetic Trees/Animal Genes : TreeFamFCER2
Homologs : HomoloGeneFCER2
Homology/Alignments : Family Browser (UCSC)FCER2
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerFCER2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FCER2
dbVarFCER2
ClinVarFCER2
1000_GenomesFCER2 
Exome Variant ServerFCER2
ExAC (Exome Aggregation Consortium)FCER2 (select the gene name)
Genetic variants : HAPMAP2208
Genomic Variants (DGV)FCER2 [DGVbeta]
Mutations
ICGC Data PortalFCER2 
TCGA Data PortalFCER2 
Broad Tumor PortalFCER2
OASIS PortalFCER2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFCER2 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch FCER2
DgiDB (Drug Gene Interaction Database)FCER2
DoCM (Curated mutations)FCER2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FCER2 (select a term)
intoGenFCER2
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)19:7753643-7764365  ENSG00000104921
CONAN: Copy Number AnalysisFCER2 
Mutations and Diseases : HGMDFCER2
OMIM151445   
MedgenFCER2
Genetic Testing Registry FCER2
NextProtP06734 [Medical]
TSGene2208
GENETestsFCER2
Huge Navigator FCER2 [HugePedia]
snp3D : Map Gene to Disease2208
BioCentury BCIQFCER2
ClinGenFCER2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2208
Chemical/Pharm GKB GenePA28058
Clinical trialFCER2
Miscellaneous
canSAR (ICR)FCER2 (select the gene name)
Probes
Litterature
PubMed122 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineFCER2
EVEXFCER2
GoPubMedFCER2
iHOPFCER2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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