Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOZRC1U)

• DOT Name: Protein TALPID3 (KIAA0586)
• Gene Name: KIAA0586
• Related Disease:
  Joubert syndrome 17
  Joubert syndrome 23
  Cholestasis
  Ciliopathy
  Hereditary hemochromatosis
  Joubert syndrome 1
  Polydactyly
  Short rib-polydactyly syndrome
  Short-rib thoracic dysplasia 14 with polydactyly
  Jeune syndrome
  Joubert syndrome
  Joubert syndrome with Jeune asphyxiating thoracic dystrophy
• UniProt ID: TALD3_HUMAN
• Pfam ID: PF15324
• Sequence:
  MPVKRLREVVSQNHGDHLVLLKDELPCVPPALSANKRLPVGTGTSLNGTSRGSSDLTSAR
  NCYQPLLENPMVSESDFSKDVAVQVLPLDKIEENNKQKANDIFISQYTMGQKDALRTVLK
  QKAQSMPVFKEVKVHLLEDAGIEKDAVTQETRISPSGIDSATTVAAATAAAIATAAPLIK
  VQSDLEAKVNSVTELLSKLQETDKHLQRVTEQQTSIQRKQEKLHCHDHEKQMNVFMEQHI
  RHLEKLQQQQIDIQTHFISAALKTSSFQPVSMPSSRAVEKYSVKPEHPNLGSCNPSLYNT
  FASKQAPLKEVEDTSFDKQKSPLETPAPRRFAPVPVSRDDELSKRENLLEEKENMEVSCH
  RGNVRLLEQILNNNDSLTRKSESSNTTSLTRSKIGWTPEKTNRFPSCEELETTKVTMQKS
  DDVLHDLGQKEKETNSMVQPKESLSMLKLPDLPQNSVKLQTTNTTRSVLKDAEKILRGVQ
  NNKKVLEENLEAIIRAKDGAAMYSLINALSTNREMSEKIRIRKTVDEWIKTISAEIQDEL
  SRTDYEQKRFDQKNQRTKKGQNMTKDIRTNTQDKTVNKSVIPRKHSQKQIEEHFRNLPMR
  GMPASSLQKERKEGLLKATTVIQDEDYMLQVYGKPVYQGHRSTLKKGPYLRFNSPSPKSR
  PQRPKVIERVKGTKVKSIRTQTDFYATKPKKMDSKMKHSVPVLPHGDQQYLFSPSREMPT
  FSGTLEGHLIPMAILLGQTQSNSDTMPPAGVIVSKPHPVTVTTSIPPSSRKVETGVKKPN
  IAIVEMKSEKKDPPQLTVQVLPSVDIDSISNSSADVLSPLSSPKEASLPPVQTWIKTPEI
  MKVDEEEVKFPGTNFDEIIDVIQEEEKCDEIPDSEPILEFNRSVKADSTKYNGPPFPPVA
  STFQPTADILDKVIERKETLENSLIQWVEQEIMSRIISGLFPVQQQIAPSISVSVSETSE
  PLTSDIVEGTSSGALQLFVDAGVPVNSNVIKHFVNEALAETIAVMLGDREAKKQGPVATG
  VSGDASTNETYLPARVCTPLPTPQPTPPCSPSSPAKECVLVKTPDSSPCDSDHDMAFPVK
  EICAEKGDDMPAIMLVNTPTVTPTTTPPPAAAVFTPTLSDISIDKLKVSSPELPKPWGDG
  DLPLEEENPNSPQEELHPRAIVMSVAKDEEPESMDFPAQPPPPEPVPFMPFPAGTKAPSP
  SQMPGSDSSTLESTLSVTVTETETLDKPISEGEILFSCGQKLAPKILEDIGLYLTNLNDS
  LSSTLHDAVEMEDDPPSEGQVIRMSHKKFHADAILSFAKQNQESAVSQQAVYHSEDLENS
  VGELSEGQRPQLTAAAENILMGHSLYMQPPVTNTQSLDQQCDPKPLSRQFDTVSGSIYED
  SCASHGPMSLGELELEPNSKLVLPTTLLTAQENDVNLPVAAEDFSQYQLKQNQDVKQVEH
  KPSQSYLRVRNKSDIAPSQQQVSPGDMDRTQIELNPYLTCVFSGGKAVPLSASQMPPAKM
  SVMLPSVNLEDCSQSLSLSTMQEDMESSGADTF
• Function: Required for ciliogenesis and sonic hedgehog/SHH signaling. Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. May play a role in early ciliogenesis in the disappearance of centriolar satellites that preceeds ciliary vesicle formation. Involved in regulation of cell intracellular organization. Involved in regulation of cell polarity. Required for asymmetrical localization of CEP120 to daughter centrioles.
• Tissue Specificity: Ubiquitously expressed . Expressed in photoreceptor cells (at protein level) .

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 17	DIS9LHZ1	Definitive	Autosomal recessive	[1]
Joubert syndrome 23	DISADFYC	Definitive	Autosomal recessive	[2]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[3]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[5]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[6]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[7]
Short rib-polydactyly syndrome	DISY2RES	Strong	Genetic Variation	[8]
Short-rib thoracic dysplasia 14 with polydactyly	DIS7WG29	Strong	Autosomal recessive	[9]
Jeune syndrome	DISLC357	moderate	Biomarker	[8]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[6]
Joubert syndrome with Jeune asphyxiating thoracic dystrophy	DIS0AZCT	Supportive	Autosomal recessive	[8]

6 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 Protein TALPID3 (KIAA0586).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Protein TALPID3 (KIAA0586).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein TALPID3 (KIAA0586).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein TALPID3 (KIAA0586).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein TALPID3 (KIAA0586).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein TALPID3 (KIAA0586).	[16]

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 Protein TALPID3 (KIAA0586).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein TALPID3 (KIAA0586).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein TALPID3 (KIAA0586).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein TALPID3 (KIAA0586).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein TALPID3 (KIAA0586).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein TALPID3 (KIAA0586).	[20]

References

• [1] Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9. doi: 10.1038/ng.3410. Epub 2015 Oct 5.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid3 ciliopathy mutant.Organogenesis. 2014 Apr-Jun;10(2):177-85. doi: 10.4161/org.28819. Epub 2014 Apr 17.
• [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] Mice with a conditional deletion of Talpid3 (KIAA0586)-a model for Joubert syndrome.J Pathol. 2019 Aug;248(4):396-408. doi: 10.1002/path.5271. Epub 2019 May 16.
• [6] KIAA0586 is Mutated in Joubert Syndrome. Hum Mutat. 2015 Sep;36(9):831-5. doi: 10.1002/humu.22821. Epub 2015 Jul 2.
• [7] Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome. Am J Hum Genet. 2015 Aug 6;97(2):311-8. doi: 10.1016/j.ajhg.2015.06.003. Epub 2015 Jul 9.
• [8] Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes. J Med Genet. 2015 Dec;52(12):830-9. doi: 10.1136/jmedgenet-2015-103316. Epub 2015 Sep 18.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] 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.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.