Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT83W5PB)

DOT Name	Tectonic-like complex member MKS1 (MKS1)
Synonyms	Meckel syndrome type 1 protein
Gene Name	MKS1
Related Disease	Bardet-Biedl syndrome 13 ( ) Meckel syndrome, type 1 ( ) Adenocarcinoma ( ) Advanced cancer ( ) Bardet-Biedl syndrome 1 ( ) Chronic obstructive pulmonary disease ( ) Dandy-Walker syndrome ( ) Depression ( ) Disorder of orbital region ( ) Fanconi anemia complementation group A ( ) Fanconi's anemia ( ) Glioblastoma multiforme ( ) Glioma ( ) HIV infectious disease ( ) Immunodeficiency ( ) Joubert syndrome 1 ( ) Joubert syndrome 28 ( ) Joubert syndrome with oculorenal defect ( ) Large cell carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lung neoplasm ( ) Lung squamous cell carcinoma ( ) McKusick-Kaufman syndrome ( ) Meckel syndrome, type 3 ( ) Neoplasm ( ) Nephronophthisis ( ) Nephropathy ( ) Non-small-cell lung cancer ( ) Renal fibrosis ( ) Teratoma ( ) Tetralogy of fallot ( ) Ulcerative colitis ( ) Kidney cancer ( ) Methicillin-resistant staphylococci infection ( ) Renal carcinoma ( ) Small-cell lung cancer ( ) Uterine corpus sarcoma ( ) Bardet biedl syndrome ( ) Joubert syndrome ( ) Joubert syndrome with ocular defect ( ) Meckel syndrome ( ) Ciliopathy ( ) Corpus callosum, agenesis of ( ) Joubert syndrome 14 ( ) Polydactyly ( )
UniProt ID	MKS1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF07162
Sequence	MAETVWSTDTGEAVYRSRDPVRNLRLRVHLQRITSSNFLHYQPAAELGKDLIDLATFRPQ PTASGHRPEEDEEEEIVIGWQEKLFSQFEVDLYQNETACQSPLDYQYRQEILKLENSGGK KNRRIFTYTDSDRYTNLEEHCQRMTTAASEVPSFLVERMANVRRRRQDRRGMEGGILKSR IVTWEPSEEFVRNNHVINTPLQTMHIMADLGPYKKLGYKKYEHVLCTLKVDSNGVITVKP DFTGLKGPYRIETEGEKQELWKYTIDNVSPHAQPEEEERERRVFKDLYGRHKEYLSSLVG TDFEMTVPGALRLFVNGEVVSAQGYEYDNLYVHFFVELPTAHWSSPAFQQLSGVTQTCTT KSLAMDKVAHFSYPFTFEAFFLHEDESSDALPEWPVLYCEVLSLDFWQRYRVEGYGAVVL PATPGSHTLTVSTWRPVELGTVAELRRFFIGGSLELEDLSYVRIPGSFKGERLSRFGLRT ETTGTVTFRLHCLQQSRAFMESSSLQKRMRSVLDRLEGFSQQSSIHNVLEAFRRARRRMQ EARESLPQDLVSPSGTLVS
Function	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in centrosome migration to the apical cell surface during early ciliogenesis. Required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Required for cell branching morphology.
Reactome Pathway	Anchoring of the basal body to the plasma membrane (R-HSA-5620912 ) Hedgehog 'off' state (R-HSA-5610787 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Bardet-Biedl syndrome 13	DIS7VVDD	Definitive	Autosomal recessive	[1]
Meckel syndrome, type 1	DIS4YWZU	Definitive	Autosomal recessive	[2]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Dandy-Walker syndrome	DIS4HC6W	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Biomarker	[8]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[7]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[9]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Genetic Variation	[11]
HIV infectious disease	DISO97HC	Strong	Biomarker	[12]
Immunodeficiency	DIS093I0	Strong	Biomarker	[12]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[13]
Joubert syndrome 28	DISX5V7P	Strong	Autosomal recessive	[14]
Joubert syndrome with oculorenal defect	DISU0IPO	Strong	Biomarker	[15]
Large cell carcinoma	DISYMCOF	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[17]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[18]
McKusick-Kaufman syndrome	DIS8JXFP	Strong	Genetic Variation	[19]
Meckel syndrome, type 3	DISJIYCP	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[21]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[22]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[23]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[5]
Teratoma	DIS6ICY4	Strong	Biomarker	[24]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[25]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[26]
Kidney cancer	DISBIPKM	moderate	Biomarker	[27]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[28]
Renal carcinoma	DISER9XT	moderate	Biomarker	[27]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[29]
Uterine corpus sarcoma	DIS502ED	moderate	Biomarker	[27]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[30]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[13]
Joubert syndrome with ocular defect	DISDJVUI	Supportive	Autosomal recessive	[13]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[31]
Ciliopathy	DIS10G4I	Limited	Biomarker	[32]
Corpus callosum, agenesis of	DISO9P40	Limited	Genetic Variation	[33]
Joubert syndrome 14	DISAHGV4	Limited	Biomarker	[34]
Polydactyly	DIS25BMZ	Limited	Biomarker	[7]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tectonic-like complex member MKS1 (MKS1).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tectonic-like complex member MKS1 (MKS1).	[36]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tectonic-like complex member MKS1 (MKS1).	[37]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tectonic-like complex member MKS1 (MKS1).	[38]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tectonic-like complex member MKS1 (MKS1).	[38]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tectonic-like complex member MKS1 (MKS1).	[40]
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⏷ Show the Full List of 6 Drug(s)

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 Tectonic-like complex member MKS1 (MKS1).	[39]
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References

1	Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet. 2007 Jun;121(5):591-9. doi: 10.1007/s00439-007-0341-3. Epub 2007 Mar 22.
2	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3	Benzyl isothiocyanate induces protective autophagy in human lung cancer cells through an endoplasmic reticulum stress-mediated mechanism.Acta Pharmacol Sin. 2017 Apr;38(4):539-550. doi: 10.1038/aps.2016.146. Epub 2017 Jan 23.
4	Osteopontin promotes cancer cell drug resistance, invasion, and lactate production and is associated with poor outcome of patients with advanced non-small-cell lung cancer.Onco Targets Ther. 2018 Sep 19;11:5933-5941. doi: 10.2147/OTT.S164007. eCollection 2018.
5	MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome.Nat Genet. 2006 Feb;38(2):155-7. doi: 10.1038/ng1714. Epub 2006 Jan 15.
6	A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
7	Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel-Gruber syndrome.Dev Biol. 2013 May 1;377(1):55-66. doi: 10.1016/j.ydbio.2013.02.015. Epub 2013 Feb 27.
8	Whether chronic pain is medically explained or not does not moderate the response to cognitive-behavioural therapy.J Psychosom Res. 2019 Jun;121:29-36. doi: 10.1016/j.jpsychores.2019.03.182. Epub 2019 Mar 26.
9	Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine.Sci Rep. 2017 Nov 8;7(1):15031. doi: 10.1038/s41598-017-15172-4.
10	The dystroglycan receptor maintains glioma stem cells in the vascular niche.Acta Neuropathol. 2019 Dec;138(6):1033-1052. doi: 10.1007/s00401-019-02069-x. Epub 2019 Aug 28.
11	The NF-B RelB protein is an oncogenic driver of mesenchymal glioma.PLoS One. 2013;8(2):e57489. doi: 10.1371/journal.pone.0057489. Epub 2013 Feb 25.
12	Congenital Tracheobronchomegaly (Mounier-Kuhn Syndrome) in a Woman with Human Immunodeficiency Virus: A Case Report.Cureus. 2017 Apr 4;9(4):e1136. doi: 10.7759/cureus.1136.
13	Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J Rare Dis. 2014 May 5;9:72. doi: 10.1186/1750-1172-9-72.
14	Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online. Hum Mutat. 2007 May;28(5):523-4. doi: 10.1002/humu.9489.
15	The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul;39(7):875-81. doi: 10.1038/ng2039. Epub 2007 Jun 10.
16	MicroRNA-133 inhibits the growth and metastasis of the human lung cancer cells by targeting epidermal growth factor receptor.J BUON. 2019 May-Jun;24(3):929-935.
17	Expression of the lncRNA Maternally Expressed Gene 3 (MEG3) Contributes to the Control of Lung Cancer Cell Proliferation by the Rb Pathway.PLoS One. 2016 Nov 10;11(11):e0166363. doi: 10.1371/journal.pone.0166363. eCollection 2016.
18	Identification of key genes and long noncoding RNAs in celecoxibtreated lung squamous cell carcinoma cell line by RNAsequencing.Mol Med Rep. 2018 May;17(5):6456-6464. doi: 10.3892/mmr.2018.8656. Epub 2018 Mar 1.
19	A female with complete lack of Mllerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?.Am J Med Genet A. 2004 Aug 15;129A(1):69-72. doi: 10.1002/ajmg.a.30071.
20	Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.Hum Mol Genet. 2009 Sep 1;18(17):3311-23. doi: 10.1093/hmg/ddp272. Epub 2009 Jun 10.
21	Endogenous arginase 2 as a potential biomarker for PEGylated arginase 1 treatment in xenograft models of squamous cell lung carcinoma.Oncogenesis. 2019 Feb 26;8(3):18. doi: 10.1038/s41389-019-0128-0.
22	MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.PLoS Biol. 2016 Mar 16;14(3):e1002416. doi: 10.1371/journal.pbio.1002416. eCollection 2016 Mar.
23	Antitumor effects of hsamiR661?p on nonsmall cell lung cancer in vivo and in vitro.Oncol Rep. 2019 May;41(5):2987-2996. doi: 10.3892/or.2019.7084. Epub 2019 Mar 21.
24	Murine pluripotent stem cells that escape differentiation inside teratomas maintain pluripotency.PeerJ. 2018 Jan 4;6:e4177. doi: 10.7717/peerj.4177. eCollection 2018.
25	Genome-wide identification of mouse congenital heart disease loci.Hum Mol Genet. 2010 Aug 15;19(16):3105-13. doi: 10.1093/hmg/ddq211. Epub 2010 May 28.
26	Faecal calprotectin level for assessing endoscopic activity and predicting future clinical course in patients with moderately active ulcerative colitis undergoing granulomonocytapheresis: a prospective cohort study.BMC Gastroenterol. 2018 Aug 1;18(1):120. doi: 10.1186/s12876-018-0853-4.
27	Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody-Drug Conjugates.J Am Chem Soc. 2018 Mar 14;140(10):3690-3711. doi: 10.1021/jacs.7b12692. Epub 2018 Jan 30.
28	Comparative genomics of community-acquired ST59 methicillin-resistant Staphylococcus aureus in Taiwan: novel mobile resistance structures with IS1216V.PLoS One. 2012;7(10):e46987. doi: 10.1371/journal.pone.0046987. Epub 2012 Oct 5.
29	miR-541 suppresses proliferation and invasion of squamous cell lung carcinoma cell lines via directly targeting high-mobility group AT-hook 2.Cancer Med. 2018 Jun;7(6):2581-2591. doi: 10.1002/cam4.1491. Epub 2018 Apr 16.
30	Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008 Apr;40(4):443-8. doi: 10.1038/ng.97. Epub 2008 Mar 9.
31	Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol. 2011 Feb;43(1):12-26. doi: 10.1007/s12035-010-8154-0. Epub 2010 Nov 27.
32	Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies.Am J Med Genet A. 2016 Dec;170(12):3289-3293. doi: 10.1002/ajmg.a.37934. Epub 2016 Aug 29.
33	MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum.Eur J Med Genet. 2016 Aug;59(8):386-91. doi: 10.1016/j.ejmg.2016.06.007. Epub 2016 Jul 1.
34	TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubertsyndrome.Nat Cell Biol. 2016 Jan;18(1):122-31. doi: 10.1038/ncb3273. Epub 2015 Nov 23.
35	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
36	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
37	Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
38	Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
39	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.
40	Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.