Details of Drug Off-Target (DOT)

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

• DOT Name: Ficolin-3 (FCN3)
• Synonyms: Collagen/fibrinogen domain-containing lectin 3 p35; Collagen/fibrinogen domain-containing protein 3; Hakata antigen
• Gene Name: FCN3
• Related Disease:
  Subarachnoid hemorrhage
  Tuberculosis
  Abdominal aortic aneurysm
  Advanced cancer
  Essential hypertension
  High blood pressure
  Immunodeficiency
  Immunodeficiency due to MASP-2 deficiency
  Leprosy
  Non-insulin dependent diabetes
  Systemic lupus erythematosus
  Systemic sclerosis
  Crohn disease
  Amyotrophic lateral sclerosis
  Bacterial infection
  Complement deficiency
  Epithelial ovarian cancer
  Fetal growth restriction
  Hepatocellular carcinoma
  Immunodeficiency due to ficolin3 deficiency
  Lupus nephritis
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: FCN3_HUMAN
• PDB ID: 2J5Z; 2J60; 2J64
• Pfam ID: PF00147
• Sequence:
  MDLLWILPSLWLLLLGGPACLKTQEHPSCPGPRELEASKVVLLPSCPGAPGSPGEKGAPG
  PQGPPGPPGKMGPKGEPGDPVNLLRCQEGPRNCRELLSQGATLSGWYHLCLPEGRALPVF
  CDMDTEGGGWLVFQRRQDGSVDFFRSWSSYRAGFGNQESEFWLGNENLHQLTLQGNWELR
  VELEDFNGNRTFAHYATFRLLGEVDHYQLALGKFSEGTAGDSLSLHSGRPFTTYDADHDS
  SNSNCAVIVHGAWWYASCYRSNLNGRYAVSEAAAHKYGIDWASGRGVGHPYRRVRMMLR
• Function: May function in innate immunity through activation of the lectin complement pathway. Calcium-dependent and GlcNAc-binding lectin. Has affinity with GalNAc, GlcNAc, D-fucose, as mono/oligosaccharide and lipopolysaccharides from S.typhimurium and S.minnesota.
• Tissue Specificity: Liver and lung. In liver it is produced by bile duct epithelial cells and hepatocytes. In lung it is produced by both ciliated bronchial epithelial cells and type II alveolar epithelial cells.
• Reactome Pathway:
  Initial triggering of complement (R-HSA-166663)
  Ficolins bind to repetitive carbohydrate structures on the target cell surface (R-HSA-2855086)
  Lectin pathway of complement activation (R-HSA-166662)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Altered Expression	[1]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[2]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[5]
Immunodeficiency	DIS093I0	Strong	Biomarker	[6]
Immunodeficiency due to MASP-2 deficiency	DISVZ6G7	Strong	Biomarker	[7]
Leprosy	DISAA4UI	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[10]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[11]
Crohn disease	DIS2C5Q8	Disputed	Genetic Variation	[12]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[13]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[9]
Complement deficiency	DISGN469	Limited	Biomarker	[14]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[15]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[17]
Immunodeficiency due to ficolin3 deficiency	DISYPUU8	Limited	Autosomal recessive	[18]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[19]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[15]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ficolin-3 (FCN3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ficolin-3 (FCN3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ficolin-3 (FCN3).	[22]

References

• [1] Changes in the Lectin Pathway Following Intracerebral or Spontaneous Subarachnoid Hemorrhage.Mol Neurobiol. 2019 Jan;56(1):78-87. doi: 10.1007/s12035-018-1066-0. Epub 2018 Apr 19.
• [2] No Strong Relationship Between Components of the Lectin Pathway of Complement and Susceptibility to Pulmonary Tuberculosis.Inflammation. 2015 Aug;38(4):1731-7. doi: 10.1007/s10753-015-0150-0.
• [3] Association of ficolin-3 with abdominal aortic aneurysm presence and progression.J Thromb Haemost. 2017 Mar;15(3):575-585. doi: 10.1111/jth.13608. Epub 2017 Feb 15.
• [4] Interactions of ficolin-3 with ovarian cancer cells.Immunobiology. 2019 Mar;224(2):316-324. doi: 10.1016/j.imbio.2019.01.002. Epub 2019 Jan 30.
• [5] A common genetic variant of FCN3/CD164L2 is associated with essential hypertension in a Chinese population.Clin Exp Hypertens. 2012;34(5):377-82. doi: 10.3109/10641963.2012.665538. Epub 2012 Apr 3.
• [6] Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency.N Engl J Med. 2009 Jun 18;360(25):2637-44. doi: 10.1056/NEJMoa0900381.
• [7] Lectin-complement pathway molecules are decreased in patients with cirrhosis and constitute the risk of bacterial infections.Liver Int. 2017 Jul;37(7):1023-1031. doi: 10.1111/liv.13368. Epub 2017 Feb 28.
• [8] Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy.PLoS Negl Trop Dis. 2017 Feb 27;11(2):e0005409. doi: 10.1371/journal.pntd.0005409. eCollection 2017 Feb.
• [9] Decreased Ficolin-3-mediated Complement Lectin Pathway Activation and Alternative Pathway Amplification During Bacterial Infections in Patients With Type 2 Diabetes Mellitus.Front Immunol. 2019 Mar 20;10:509. doi: 10.3389/fimmu.2019.00509. eCollection 2019.
• [10] Ficolin-3 Deficiency Is Associated with Disease and an Increased Risk of Systemic Lupus Erythematosus.J Clin Immunol. 2019 May;39(4):421-429. doi: 10.1007/s10875-019-00627-2. Epub 2019 May 1.
• [11] Serum H-ficolin levels: Clinical association with interstitial lung disease in patients with systemic sclerosis.J Dermatol. 2017 Oct;44(10):1168-1171. doi: 10.1111/1346-8138.13877. Epub 2017 Apr 22.
• [12] Genetic polymorphisms of mannan binding lectin (MBL), serum levels of MBL, the MBL associated serine protease and H-ficolin in patients with Crohn's disease.Gut. 2007 Feb;56(2):311-2. doi: 10.1136/gut.2006.109504.
• [13] Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis.Mol Immunol. 2018 Oct;102:14-25. doi: 10.1016/j.molimm.2018.06.007. Epub 2018 Jun 20.
• [14] Primary Ficolin-3 deficiency--Is it associated with increased susceptibility to infections?.Immunobiology. 2015 Jun;220(6):711-3. doi: 10.1016/j.imbio.2015.01.003. Epub 2015 Jan 19.
• [15] Ficolin-2 and ficolin-3 in women with malignant and benign ovarian tumours.Cancer Immunol Immunother. 2013 Aug;62(8):1411-9. doi: 10.1007/s00262-013-1445-3. Epub 2013 Jun 7.
• [16] Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia.Am J Reprod Immunol. 2019 Apr;81(4):e13092. doi: 10.1111/aji.13092. Epub 2019 Feb 23.
• [17] Elevated serum activity of MBL and ficolin-2 as biomarkers for progression to hepatocellular carcinoma in chronic HCV infection.Virology. 2019 Apr;530:99-106. doi: 10.1016/j.virol.2019.02.002. Epub 2019 Feb 12.
• [18] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [19] Autoantibodies Targeting Ficolin-2 in Systemic Lupus Erythematosus Patients With Active Nephritis.Arthritis Care Res (Hoboken). 2018 Aug;70(8):1263-1268. doi: 10.1002/acr.23449. Epub 2018 Jun 21.
• [20] 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.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] 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.