Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIFXFWL)

• DOT Name: Fc receptor-like protein 3 (FCRL3)
• Synonyms: FcR-like protein 3; FcRL3; Fc receptor homolog 3; FcRH3; IFGP family protein 3; hIFGP3; Immune receptor translocation-associated protein 3; MAIA; SH2 domain-containing phosphatase anchor protein 2; CD antigen CD307c
• Gene Name: FCRL3
• Related Disease:
  Primary biliary cholangitis
  Acute coronary syndrome
  Acute intermittent hepatic porphyria
  Allergic rhinitis
  Alopecia
  Alopecia areata
  Asthma
  Autoimmune hepatitis
  Autoimmune thyroid disease
  Behcet disease
  Chronic graft versus host disease
  Crohn disease
  Endometriosis
  Hashimoto thyroiditis
  IgA nephropathy
  Inflammatory bowel disease
  Irritable bowel syndrome
  Juvenile idiopathic arthritis
  Leukopenia
  Multiple sclerosis
  Sezary syndrome
  Small lymphocytic lymphoma
  Tendinopathy
  Type-1 diabetes
  Ulcerative colitis
  Immune system disorder
  Advanced cancer
  Graves disease
  Neoplasm
  Neuromyelitis optica
  Primary cutaneous T-cell lymphoma
• UniProt ID: FCRL3_HUMAN
• Pfam ID: PF00047 ; PF13895 ; PF13927
• Sequence:
  MLLWLLLLILTPGREQSGVAPKAVLLLNPPWSTAFKGEKVALICSSISHSLAQGDTYWYH
  DEKLLKIKHDKIQITEPGNYQCKTRGSSLSDAVHVEFSPDWLILQALHPVFEGDNVILRC
  QGKDNKNTHQKVYYKDGKQLPNSYNLEKITVNSVSRDNSKYHCTAYRKFYILDIEVTSKP
  LNIQVQELFLHPVLRASSSTPIEGSPMTLTCETQLSPQRPDVQLQFSLFRDSQTLGLGWS
  RSPRLQIPAMWTEDSGSYWCEVETVTHSIKKRSLRSQIRVQRVPVSNVNLEIRPTGGQLI
  EGENMVLICSVAQGSGTVTFSWHKEGRVRSLGRKTQRSLLAELHVLTVKESDAGRYYCAA
  DNVHSPILSTWIRVTVRIPVSHPVLTFRAPRAHTVVGDLLELHCESLRGSPPILYRFYHE
  DVTLGNSSAPSGGGASFNLSLTAEHSGNYSCDADNGLGAQHSHGVSLRVTVPVSRPVLTL
  RAPGAQAVVGDLLELHCESLRGSFPILYWFYHEDDTLGNISAHSGGGASFNLSLTTEHSG
  NYSCEADNGLGAQHSKVVTLNVTGTSRNRTGLTAAGITGLVLSILVLAAAAALLHYARAR
  RKPGGLSATGTSSHSPSECQEPSSSRPSRIDPQEPTHSKPLAPMELEPMYSNVNPGDSNP
  IYSQIWSIQHTKENSANCPMMHQEHEELTVLYSELKKTHPDDSAGEASSRGRAHEEDDEE
  NYENVPRVLLASDH
• Function: Promotes TLR9-induced B-cell proliferation, activation and survival but inhibits antibody production and suppresses plasma cell differentiation. Enhances activation of NF-kappa-B and MAPK signaling pathways in TLR9 stimulated B-cells. Has inhibitory potentional on B-cell receptor (BCR)-mediated signaling, possibly through association with SH2 domain-containing phosphatases. Inhibits cell tyrosine phosphorylation, calcium mobilization and activation-induced cell death induced through BCR signaling. Regulatory T-cells expressing FCRL3 exhibit a memory phenotype, are relatively nonresponsive to antigenic stimulation in presence of IL2 and have reduced capacity to suppress the proliferation of effector T-cells. Acts as a human-specific epitope on the cell surface of oocytes (oolemma) and plays a role during sperm-egg adhesion and fusion. Interacts with the IZUMO1-IZUMO1R/JUNO sperm-egg complex and replaces IZUMO1R/JUNO as IZUMO1 receptor during fertilization, thereby permitting species-specific gamete fusion.
• Tissue Specificity: Primarily expressed in secondary lymphoid tissues by mature subsets of B-cells. Low expression on transitional B cells which increases to higher surface expression on mature and memory B-cells with innate-like features (at protein level) . Expressed a low levels in naive and germinal center B-cells but also expressed in NK cells (at protein level) . Expressed in unfertilized oocytes (at protein level) . Expressed in a population of thymically derived naturally occurring regulatory T-cells that exhibits a memory phenotype, specialized in suppressing immune response to self-antigens . Detected in spleen, lymph node, peripheral blood lymphocytes, thymus, bone marrow, kidney, salivary gland, adrenal gland and uterus.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[1]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[2]
Acute intermittent hepatic porphyria	DIS80J7E	Strong	Genetic Variation	[3]
Allergic rhinitis	DIS3U9HN	Strong	Genetic Variation	[4]
Alopecia	DIS37HU4	Strong	Genetic Variation	[5]
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[5]
Asthma	DISW9QNS	Strong	Genetic Variation	[4]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[6]
Autoimmune thyroid disease	DISIHC6A	Strong	Altered Expression	[7]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[8]
Chronic graft versus host disease	DIS1MM9J	Strong	Biomarker	[9]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[10]
Endometriosis	DISX1AG8	Strong	Biomarker	[11]
Hashimoto thyroiditis	DIS77CDF	Strong	Altered Expression	[7]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[12]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[13]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[13]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[14]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[15]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[16]
Sezary syndrome	DISFMTC7	Strong	Altered Expression	[17]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[18]
Tendinopathy	DISJH7UX	Strong	Genetic Variation	[19]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[20]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[13]
Immune system disorder	DISAEGPH	moderate	Biomarker	[21]
Advanced cancer	DISAT1Z9	Disputed	Genetic Variation	[22]
Graves disease	DISU4KOQ	Limited	Genetic Variation	[23]
Neoplasm	DISZKGEW	Limited	Altered Expression	[24]
Neuromyelitis optica	DISBFGKL	Limited	Genetic Variation	[25]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Altered Expression	[24]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Fc receptor-like protein 3 (FCRL3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Fc receptor-like protein 3 (FCRL3).	[31]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Fc receptor-like protein 3 (FCRL3).	[27]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Fc receptor-like protein 3 (FCRL3).	[28]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Fc receptor-like protein 3 (FCRL3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fc receptor-like protein 3 (FCRL3).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Fc receptor-like protein 3 (FCRL3).	[28]

References

• [1] Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients.Tissue Antigens. 2011 Mar;77(3):239-43. doi: 10.1111/j.1399-0039.2010.01600.x.
• [2] MHC2TA and FCRL3 genes are not associated with rheumatoid arthritis in Mexican patients.Rheumatol Int. 2016 Feb;36(2):249-54. doi: 10.1007/s00296-015-3358-2. Epub 2015 Sep 8.
• [3] Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients.Am J Gastroenterol. 2008 Mar;103(3):588-94. doi: 10.1111/j.1572-0241.2007.01750.x.
• [4] Genetic risk of FCRL3 and FCRL5 polymorphisms in children with asthma and allergic rhinitis in a Chinese Han population.Int J Pediatr Otorhinolaryngol. 2019 May;120:58-63. doi: 10.1016/j.ijporl.2019.02.015. Epub 2019 Feb 5.
• [5] Investigation of the functional variant c.-169T > C of the Fc receptor-like 3 (FCRL3) gene in alopecia areata.Int J Immunogenet. 2006 Dec;33(6):393-5. doi: 10.1111/j.1744-313X.2006.00633.x.
• [6] Lack of association between FCRL3 and FcgammaRII polymorphisms in Japanese type 1 autoimmune hepatitis.Clin Immunol. 2007 Mar;122(3):338-42. doi: 10.1016/j.clim.2006.08.012. Epub 2006 Oct 3.
• [7] Expression of TIGIT and FCRL3 is Altered in T Cells from Patients with Distinct Patterns of Chronic Autoimmune Thyroiditis.Exp Clin Endocrinol Diabetes. 2019 May;127(5):281-288. doi: 10.1055/a-0597-8948. Epub 2018 Jun 11.
• [8] Single Nucleotide Polymorphisms of FCRL3 in Iranian Patients with Behcet's Disease.Iran J Public Health. 2019 Jun;48(6):1133-1139.
• [9] Association of autoimmune disease-related gene polymorphisms with chronic graft-versus-host disease.Br J Haematol. 2007 Nov;139(3):458-63. doi: 10.1111/j.1365-2141.2007.06797.x. Epub 2007 Sep 14.
• [10] FcRL3 gene promoter variant is associated with peripheral arthritis in Crohn's disease.Inflamm Bowel Dis. 2009 Sep;15(9):1351-7. doi: 10.1002/ibd.20895.
• [11] Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk: An Independent Study in Han Chinese.Medicine (Baltimore). 2015 Sep;94(35):e1168. doi: 10.1097/MD.0000000000001168.
• [12] Three SNPs of FCRL3 and one SNP of MTMR3 are associated with immunoglobulin A nephropathy risk.Immunobiology. 2020 Jan;225(1):151869. doi: 10.1016/j.imbio.2019.11.004. Epub 2019 Nov 18.
• [13] Epistatic interaction between FCRL3 and MHC in Spanish patients with IBD.Tissue Antigens. 2007 Apr;69(4):313-7. doi: 10.1111/j.1399-0039.2007.00816.x.
• [14] The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases.Ann Rheum Dis. 2008 Sep;67(9):1287-91. doi: 10.1136/ard.2007.077826. Epub 2007 Dec 7.
• [15] Disease phenotypes and gender association of FCRL3 single-nucleotide polymorphism -169T/C in Taiwanese patients with systemic lupus erythematosus and rheumatoid arthritis.J Rheumatol. 2011 Feb;38(2):264-70. doi: 10.3899/jrheum.100437. Epub 2010 Nov 15.
• [16] Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.Mult Scler. 2016 Dec;22(14):1783-1793. doi: 10.1177/1352458516635873. Epub 2016 Feb 26.
• [17] Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Szary syndrome.Leuk Lymphoma. 2019 Aug;60(8):1899-1907. doi: 10.1080/10428194.2018.1564827. Epub 2019 Jan 14.
• [18] Cluster analysis of immunophenotypic data: the example of chronic lymphocytic leukemia.Immunol Lett. 2011 Jan 30;134(2):137-44. doi: 10.1016/j.imlet.2010.09.017. Epub 2010 Oct 13.
• [19] Fc receptor-like 3 (-169T>C) polymorphism increases the risk of tendinopathy in volleyball athletes: a case control study.BMC Med Genet. 2018 Jul 18;19(1):119. doi: 10.1186/s12881-018-0633-6.
• [20] Coincidence of PTPN22 c.1858CC and FCRL3 -169CC genotypes as a biomarker of preserved residual -cell function in children with type 1 diabetes.Pediatr Diabetes. 2017 Dec;18(8):696-705. doi: 10.1111/pedi.12429. Epub 2016 Sep 12.
• [21] Juvenile rheumatoid arthritis and asthma, but not childhood-onset systemic lupus erythematosus are associated with FCRL3 polymorphisms in Mexicans.Mol Immunol. 2013 Apr;53(4):374-8. doi: 10.1016/j.molimm.2012.09.004. Epub 2012 Oct 13.
• [22] CD164 identifies CD4(+) T cells highly expressing genes associated with malignancy in Szary syndrome: the Szary signature genes, FCRL3, Tox, and miR-214.Arch Dermatol Res. 2017 Jan;309(1):11-19. doi: 10.1007/s00403-016-1698-8. Epub 2016 Oct 20.
• [23] Genetic association of Fc receptor-like glycoprotein with susceptibility to Graves' disease in a Chinese Han population.Immunobiology. 2016 Jan;221(1):56-62. doi: 10.1016/j.imbio.2015.08.002. Epub 2015 Aug 18.
• [24] CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Szary syndrome patients.J Invest Dermatol. 2014 Jan;134(1):229-236. doi: 10.1038/jid.2013.279. Epub 2013 Jun 21.
• [25] Significant Association Between Fc Receptor-Like 3 Polymorphisms (-1901A>G and -658C>T) and Neuromyelitis Optica (NMO) Susceptibility in the Chinese Population.Mol Neurobiol. 2016 Jan;53(1):686-694. doi: 10.1007/s12035-014-9036-7. Epub 2015 Jan 10.
• [26] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [27] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [28] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [29] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [30] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [31] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.