Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC52E7V)

• DOT Name: C2 domain-containing protein 3 (C2CD3)
• Gene Name: C2CD3
• Related Disease:
  Joubert syndrome
  Neoplasm
  Orofaciodigital syndrome type 14
  Ciliopathy
  Gastrointestinal stromal tumour
  Isolated congenital microcephaly
  Orofaciodigital syndrome
  Orofaciodigital syndrome I
  Orofaciodigital syndrome type II
  Osteochondrodysplasia
  Skeletal dysplasia
  Asphyxiating thoracic dystrophy 3
• UniProt ID: C2CD3_HUMAN
• Pfam ID: PF00168
• Sequence:
  MKQRKGQGSGGSRGRKKRGLSDISPSTSLPPLVEGQLRCFLKLTVNRVIWKIAKPPTCVL
  VRVRWWGETSDGTLFCPRDALQTEPKAVRTTTRYAIRCGPKQFTSYLTDMAVLVLEVITK
  LDGLPIGRVQINGLAQLSPTHQINGFFTIVSSTSKKLGELQVSLALEPLSETYDSYHPLP
  TTDMTENVLLSKQGFRENTEPSSTQFQVPSRPRDIHTIKIDGKELAANSSRSTTPRGKDH
  VCFAENPDTIKDSSFGLQHSLNSGQSLESVTLKGRAPRKQMSLLNSSEFQPQIRTVAKSH
  SDSCILSSNNLPTKDLLSALLEQGNKLRNAMVISAMKSSPETSMLLDQVHPPINEDSLRA
  STQIRAFSRNRFKDHIEDHLLPSTENTFWRHDTKADTRAIQLLLGSAELSQGNFWDGLGS
  PPDSPSPGSDVYCISELNDPQYDQSLLENLFYTAPKSDTSISDFLSEEDDIVPSKKISQS
  TALARSSKVLESSDHKLKKRSAGKRNRNLVEQQMLSETPEDAQTMTLSVDRLALLGRTHS
  VRIIIETMGVPPDSPQMTPGKKSYAGPPPKVTTAKKRTFFVEYHFPVGFSESGLGKTALI
  TEVVRLASSKITDGKVKFQQRFVFPVQFGGPMIEHWWNSNLTFQIYVKKTPQKKPEVIGS
  VSLSLRAVIQSELLSFSDQLPVQQENGQSPFGPLKVTMELITDNKDFTGINTKLSGNTHY
  TPLCAPTSPNKALPELNQDMTCTKNPQNLNQIHEETAKKAQNLVLPNRKSPSPVAPHPST
  FVATPASHNLVNQTNGTTKESALLLHVLLMVPDGKDFISGESEKQSPCNVYLNCKLFSTE
  EVTRSVIAWGTTQPVFNFSQVIPVSLSSKYLERLKNNVMVIETWNKVRSPGQDKLLGLVK
  LPLHQFYMSFKDAKISRLLLDAQYPVVAVDSYMPVIDVFSGHQNGSLRVFLAMGSSNQIM
  ALQRLKNEEGTLPPFSPRPAHFLDQPTAASVAMAEDRGNGLMEHCFEIHIEMVKGLAPLQ
  ATVWGEADCYVQYYFPVQHSQSSVLKGPEFLENGITLKPFRTATTLCVPDPIFNSEHHHS
  LLLPAEVPVQRLLLSAFSAQGLVPGGGVQFEIWCRYYYPNVRDQKVAKGTLPLSRICAMV
  TTQHREDVGIQTFNLPLTPRIENRKELRNQSSGLLDVGLRYRRSPRTAEGVLAARTVSIS
  VQIIRACGLQAAAKALAEREPALQFSATVGVNASVTTHLSFLPQGEQRRTHPVACSFCPE
  FSHHVEFTCNLVTQHCSGEACFLAELLEFAEVIFAVYHENTKSASDIISIESCKEYLLGV
  VKVPTKELLIKRSGITGWYPIILPEDGGLPHGLELMQKIVGGLELSISFTHRGDRERVLE
  AAEHLGWSFENSLKDFVRMDEGEPATVTISTPRLWLPIHCVLLAGHNHIHKNTYCYLRYK
  FYDHEAFWTPLKKPKESVNKKQIMVTFKASKRAEVTRGPSLLWYFREERLEIQVWRAYGN
  DSVERPHQTDSWIGSAYVDLARLGERSARTLTVSGVYPLFGRNASNLSGAALRVHVVLSS
  LSSHLEPTHELDSMDCSSHSESEQLPRRNDEVQLSPPEVISCHQKSPASTQVPCSSTTAE
  VRLTQEGPADLDGTFAVSILVERAMHLSLKGSPLTERKVSIPSCCVSFATADESSPVYTQ
  VVENTDSPIWNFQQQSRLSKELLLDPQQTLVFKVWHKGDEERVIGFASVDLSPLLSGFQF
  VCGWYNITDFSGECQGQIKVAVSPLESLIHFKEERQARRGVETSKSLIPIYSPFSFPASD
  TYAAFSSHMARQTLDQLAHASSKELDFSSPGRSDTTRSQASRHEEHVQNIRRFHESLHLQ
  GEAPLPCDDKLTTSPLSSQTSILTSLRKNLSELDQIQRYFRQKLTKPFLPLSPQTQTAIS
  QHQESCRDHLGPGASSLDPGSQCILEKSSNLVLQVSSLITDLQTITRDSQAALSSHRARS
  RSNKATTLPDAQDTEALQERCTMPDEPLVRAPDKGTDSPSPPPLEETSNGGRMLHESLRH
  AVPITRMQSSEDTEAGPAYSDEDYEEDIIEPRTLNEITTVTDKTSPWSSVISDTSEVISP
  QPDEVQREGPSCPSPGPFCREELMVKSSFLSSPERAVNPHLPRQGSPSQSLVACECEASK
  ARVGGESASANPQPIPCPTLSGAQQSSTFVGWSSPQTDQNKEPKSEAPAENEAATSELGD
  SADSFKKLPLNLASQSRRENHKGPPIDSSDIRQRQVTTGSETSTKQSLLLPGPIVVPNFF
  LPPQQLEASLRMLSLSATLPPAATTDQDKSEATRGALSQRPCRPRPNSLPLNLPEEETLR
  IARIFSSQYSQKD
• Function: Component of the centrioles that acts as a positive regulator of centriole elongation. Promotes assembly of centriolar distal appendage, a structure at the distal end of the mother centriole that acts as an anchor of the cilium, and is required for recruitment of centriolar distal appendages proteins CEP83, SCLT1, CEP89, FBF1 and CEP164. Not required for centriolar satellite integrity or RAB8 activation. Required for primary cilium formation. Required for sonic hedgehog/SHH signaling and for proteolytic processing of GLI3.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome	DIS7P5CO	Definitive	CausalMutation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Orofaciodigital syndrome type 14	DIS2OCWG	Definitive	Autosomal recessive	[3]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Orofaciodigital syndrome	DISSB296	Strong	Genetic Variation	[6]
Orofaciodigital syndrome I	DIST27XL	Strong	Biomarker	[6]
Orofaciodigital syndrome type II	DIS4O7OQ	Strong	Biomarker	[7]
Osteochondrodysplasia	DIS9SPWW	moderate	Genetic Variation	[6]
Skeletal dysplasia	DIS5Z8U6	moderate	Genetic Variation	[6]
Asphyxiating thoracic dystrophy 3	DISFN8TK	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of C2 domain-containing protein 3 (C2CD3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C2 domain-containing protein 3 (C2CD3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of C2 domain-containing protein 3 (C2CD3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of C2 domain-containing protein 3 (C2CD3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of C2 domain-containing protein 3 (C2CD3).	[10]

References

• [1] Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.
• [2] Search for chromosome rearrangements: new approaches toward discovery of novel translocations in head and neck squamous cell carcinoma.Head Neck. 2013 Jun;35(6):831-5. doi: 10.1002/hed.23037. Epub 2012 Jul 17.
• [3] 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.
• [4] CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis.Sci Rep. 2019 Apr 15;9(1):6037. doi: 10.1038/s41598-019-42577-0.
• [5] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [6] Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function.Sci Rep. 2016 Apr 20;6:24083. doi: 10.1038/srep24083.
• [7] The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation. Nat Genet. 2014 Aug;46(8):905-11. doi: 10.1038/ng.3031. Epub 2014 Jul 6.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.