Details of Drug Off-Target (DOT)

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

• DOT Name: Tetratricopeptide repeat protein 8 (TTC8)
• Synonyms: TPR repeat protein 8; Bardet-Biedl syndrome 8 protein
• Gene Name: TTC8
• Related Disease:
  Bardet-Biedl syndrome 8
  Retinitis pigmentosa 51
  Bardet-Biedl syndrome 1
  Hydrocephalus
  Nijmegen breakage syndrome
  Bardet biedl syndrome
  Retinitis pigmentosa
• UniProt ID: TTC8_HUMAN
• Pfam ID: PF13432 ; PF13181
• Sequence:
  MSSEMEPLLLAWSYFRRRKFQLCADLCTQMLEKSPYDQEPDPELPVHQAAWILKARALTE
  MVYIDEIDVDQEGIAEMMLDENAIAQVPRPGTSLKLPGTNQTGGPSQAVRPITQAGRPIT
  GFLRPSTQSGRPGTMEQAIRTPRTAYTARPITSSSGRFVRLGTASMLTSPDGPFINLSRL
  NLTKYSQKPKLAKALFEYIFHHENDVKTIHLEDVVLHLGIYPFLLRNKNHIEKNALDLAA
  LSTEHSQYKDWWWKVQIGKCYYRLGMYREAEKQFKSALKQQEMVDTFLYLAKVYVSLDQP
  VTALNLFKQGLDKFPGEVTLLCGIARIYEEMNNMSSAAEYYKEVLKQDNTHVEAIACIGS
  NHFYSDQPEIALRFYRRLLQMGIYNGQLFNNLGLCCFYAQQYDMTLTSFERALSLAENEE
  EAADVWYNLGHVAVGIGDTNLAHQCFRLALVNNNNHAEAYNNLAVLEMRKGHVEQARALL
  QTASSLAPHMYEPHFNFATISDKIGDLQRSYVAAQKSEAAFPDHVDTQHLIKQLRQHFAM
  L
• Function: The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for proper BBSome complex assembly and its ciliary localization.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet-Biedl syndrome 8	DISAICYU	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 51	DISTG03T	Definitive	Autosomal recessive	[2]
Bardet-Biedl syndrome 1	DISRLPZE	Strong	Biomarker	[2]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[3]
Nijmegen breakage syndrome	DIS98HVL	Strong	Biomarker	[4]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[6]

2 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 Tetratricopeptide repeat protein 8 (TTC8).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Tetratricopeptide repeat protein 8 (TTC8).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tetratricopeptide repeat protein 8 (TTC8).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tetratricopeptide repeat protein 8 (TTC8).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tetratricopeptide repeat protein 8 (TTC8).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tetratricopeptide repeat protein 8 (TTC8).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tetratricopeptide repeat protein 8 (TTC8).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tetratricopeptide repeat protein 8 (TTC8).	[14]

References

• [1] 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.
• [2] A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. Am J Hum Genet. 2010 May 14;86(5):805-12. doi: 10.1016/j.ajhg.2010.04.001. Epub 2010 May 6.
• [3] Absence of BBSome function leads to astrocyte reactivity in the brain.Mol Brain. 2019 May 9;12(1):48. doi: 10.1186/s13041-019-0466-z.
• [4] BBS7 and TTC8 (BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population.Hum Mutat. 2009 Jul;30(7):E737-46. doi: 10.1002/humu.21040.
• [5] Bardet-Biedl Syndrome Overview. 2003 Jul 14 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.