Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC427QQ)

• DOT Name: Protein fuzzy homolog (FUZ)
• Gene Name: FUZ
• Related Disease:
  Neoplasm
  Androgen insensitivity syndrome
  Anencephaly
  Autism spectrum disorder
  Benign prostatic hyperplasia
  Helminth infection
  Hermansky-Pudlak syndrome
  Hydrocephalus
  Non-small-cell lung cancer
  Obesity
  Schistosomiasis
  Hyperparathyroidism 2 with jaw tumors
  Tuberous sclerosis
  Ebola virus infection
  Neural tube defects, susceptibility to
  Tardive dyskinesia
• UniProt ID: FUZZY_HUMAN
• PDB ID: 7Q3D
• Pfam ID: PF19036 ; PF19037 ; PF19038
• Sequence:
  MGEEGTGGTVHLLCLAASSGVPLFCRSSRGGAPARQQLPFSVIGSLNGVHMFGQNLEVQL
  SSARTENTTVVWKSFHDSITLIVLSSEVGISELRLERLLQMVFGAMVLLVGLEELTNIRN
  VERLKKDLRASYCLIDSFLGDSELIGDLTQCVDCVIPPEGSLLQEALSGFAEAAGTTFVS
  LVVSGRVVAATEGWWRLGTPEAVLLPWLVGSLPPQTARDYPVYLPHGSPTVPHRLLTLTL
  LPSLELCLLCGPSPPLSQLYPQLLERWWQPLLDPLRACLPLGPRALPSGFPLHTDILGLL
  LLHLELKRCLFTVEPLGDKEPSPEQRRRLLRNFYTLVTSTHFPPEPGPPEKTEDEVYQAQ
  LPRACYLVLGTEEPGTGVRLVALQLGLRRLLLLLSPQSPTHGLRSLATHTLHALTPLL
• Function: Probable planar cell polarity effector involved in cilium biogenesis. May regulate protein and membrane transport to the cilium. Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies. May regulate the morphogenesis of hair follicles which depends on functional primary cilia.
• Reactome Pathway: Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[2]
Anencephaly	DISIYW6T	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Helminth infection	DIS7CGKY	Strong	Biomarker	[6]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[7]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Schistosomiasis	DIS6PD44	Strong	Biomarker	[11]
Hyperparathyroidism 2 with jaw tumors	DISWEGI1	moderate	Genetic Variation	[12]
Tuberous sclerosis	DISEMUGZ	moderate	Genetic Variation	[13]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[14]
Neural tube defects, susceptibility to	DISHA84K	Limited	Unknown	[15]
Tardive dyskinesia	DISKA5RC	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein fuzzy homolog (FUZ).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein fuzzy homolog (FUZ).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein fuzzy homolog (FUZ).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein fuzzy homolog (FUZ).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein fuzzy homolog (FUZ).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein fuzzy homolog (FUZ).	[21]

References

• [1] Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2.Tumour Biol. 2014 Dec;35(12):12583-92. doi: 10.1007/s13277-014-2579-4. Epub 2014 Sep 6.
• [2] Promoter-dependent activity on androgen receptor N-terminal domain mutations in androgen insensitivity syndrome.Sex Dev. 2014;8(6):339-49. doi: 10.1159/000369266. Epub 2014 Dec 6.
• [3] Glutamate carboxypeptidase II gene polymorphisms and neural tube defects in a high-risk Chinese population.Metab Brain Dis. 2012 Mar;27(1):59-65. doi: 10.1007/s11011-011-9272-8. Epub 2011 Nov 29.
• [4] Does high-dose gestational folic acid increase the risk for autism? The birth order hypothesis.Med Hypotheses. 2019 Nov;132:109350. doi: 10.1016/j.mehy.2019.109350. Epub 2019 Jul 31.
• [5] Androgen receptor isoforms expression in benign prostatic hyperplasia and primary prostate cancer.PLoS One. 2018 Jul 20;13(7):e0200613. doi: 10.1371/journal.pone.0200613. eCollection 2018.
• [6] Initiating NTD programs targeting schistosomiasis and soil-transmitted helminthiasis in two provinces of the Democratic Republic of the Congo: Establishment of baseline prevalence for mass drug administration.Acta Trop. 2017 Feb;166:177-185. doi: 10.1016/j.actatropica.2016.11.023. Epub 2016 Nov 22.
• [7] Hexa-Longin domain scaffolds for inter-Rab signalling.Bioinformatics. 2020 Feb 15;36(4):990-993. doi: 10.1093/bioinformatics/btz739.
• [8] "Isolated" hydrocephalus in families of spina bifida and anencephaly: a coincidence?.Neuropediatrics. 1989 Nov;20(4):220-2. doi: 10.1055/s-2008-1071297.
• [9] In vitro study of FUZ as a novel potential therapeutic target in non-small-cell lung cancer.Life Sci. 2018 Mar 15;197:91-100. doi: 10.1016/j.lfs.2018.02.007. Epub 2018 Feb 6.
• [10] Uncoupling protein 2 polymorphisms as risk factors for NTDs.Birth Defects Res A Clin Mol Teratol. 2009 Feb;85(2):156-60. doi: 10.1002/bdra.20520.
• [11] Schistosomiasis is more prevalent than previously thought: what does it mean for public health goals, policies, strategies, guidelines and intervention programs?.Infect Dis Poverty. 2017 Mar 22;6(1):63. doi: 10.1186/s40249-017-0275-5.
• [12] Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.Sci Rep. 2017 Nov 15;7(1):15638. doi: 10.1038/s41598-017-15715-9.
• [13] Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.Nat Commun. 2013;4:2135. doi: 10.1038/ncomms3135.
• [14] Commentary: restarting NTD programme activities after the Ebola outbreak in Liberia.Infect Dis Poverty. 2017 May 1;6(1):52. doi: 10.1186/s40249-017-0272-8.
• [15] Mutations in the planar cell polarity gene, Fuzzy, are associated with neural tube defects in humans. Hum Mol Genet. 2011 Nov 15;20(22):4324-33. doi: 10.1093/hmg/ddr359. Epub 2011 Aug 12.
• [16] Resting-state Brain Activity Changes Associated with Tardive Dyskinesia in Patients with Schizophrenia: Fractional Amplitude of Low-frequency Fluctuation Decreased in the Occipital Lobe.Neuroscience. 2018 Aug 10;385:237-245. doi: 10.1016/j.neuroscience.2018.06.014. Epub 2018 Jun 20.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [20] 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.
• [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] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.