Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXA87U)

• DOT Name: Tetratricopeptide repeat protein 21B (TTC21B)
• Synonyms: TPR repeat protein 21B; Intraflagellar transport 139 homolog
• Gene Name: TTC21B
• Related Disease:
  Asphyxiating thoracic dystrophy 4
  Nephronophthisis 12
  Ataxia-telangiectasia
  Chronic renal failure
  Ciliopathy
  Cystic kidney disease
  Drug dependence
  End-stage renal disease
  Focal segmental glomerulosclerosis
  High blood pressure
  Interstitial nephritis
  Lung carcinoma
  Myopia
  Nephronophthisis
  Substance abuse
  Substance dependence
  Isolated congenital microcephaly
  Nephropathy
  Jeune syndrome
  Nephronophthisis 2
• UniProt ID: TT21B_HUMAN
• PDB ID: 8BBE; 8BBG; 8FGW
• Pfam ID: PF14559 ; PF13176 ; PF13181
• Sequence:
  MDSQELKTLINYYCQERYFHHVLLVASEGIKRYGSDPVFRFYHAYGTLMEGKTQEALREF
  EAIKNKQDVSLCSLLALIYAHKMSPNPDREAILESDARVKEQRKGAGEKALYHAGLFLWH
  IGRHDKAREYIDRMIKISDGSKQGHVLKAWLDITRGKEPYTKKALKYFEEGLQDGNDTFA
  LLGKAQCLEMRQNYSGALETVNQIIVNFPSFLPAFVKKMKLQLALQDWDQTVETAQRLLL
  QDSQNVEALRMQALYYVCREGDIEKASTKLENLGNTLDAMEPQNAQLFYNITLAFSRTCG
  RSQLILQKIQTLLERAFSLNPQQSEFATELGYQMILQGRVKEALKWYKTAMTLDETSVSA
  LVGFIQCQLIEGQLQDADQQLEFLNEIQQSIGKSAELIYLHAVLAMKKNKRQEEVINLLN
  DVLDTHFSQLEGLPLGIQYFEKLNPDFLLEIVMEYLSFCPMQPASPGQPLCPLLRRCISV
  LETVVRTVPGLLQTVFLIAKVKYLSGDIEAAFNNLQHCLEHNPSYADAHLLLAQVYLSQE
  KVKLCSQSLELCLSYDFKVRDYPLYHLIKAQSQKKMGEIADAIKTLHMAMSLPGMKRIGA
  STKSKDRKTEVDTSHRLSIFLELIDVHRLNGEQHEATKVLQDAIHEFSGTSEEVRVTIAN
  ADLALAQGDIERALSILQNVTAEQPYFIEAREKMADIYLKHRKDKMLYITCFREIAERMA
  NPRSFLLLGDAYMNILEPEEAIVAYEQALNQNPKDGTLASKMGKALIKTHNYSMAITYYE
  AALKTGQKNYLCYDLAELLLKLKWYDKAEKVLQHALAHEPVNELSALMEDGRCQVLLAKV
  YSKMEKLGDAITALQQARELQARVLKRVQMEQPDAVPAQKHLAAEICAEIAKHSVAQRDY
  EKAIKFYREALVHCETDNKIMLELARLYLAQDDPDSCLRQCALLLQSDQDNEAATMMMAD
  LMFRKQDYEQAVFHLQQLLERKPDNYMTLSRLIDLLRRCGKLEDVPRFFSMAEKRNSRAK
  LEPGFQYCKGLYLWYTGEPNDALRHFNKARKDRDWGQNALYNMIEICLNPDNETVGGEVF
  ENLDGDLGNSTEKQESVQLAVRTAEKLLKELKPQTVQGHVQLRIMENYCLMATKQKSNVE
  QALNTFTEIAASEKEHIPALLGMATAYMILKQTPRARNQLKRIAKMNWNAIDAEEFEKSW
  LLLADIYIQSAKYDMAEDLLKRCLRHNRSCCKAYEYMGYIMEKEQAYTDAALNYEMAWKY
  SNRTNPAVGYKLAFNYLKAKRYVDSIDICHQVLEAHPTYPKIRKDILDKARASLRP
• Function: Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs). Essential for retrograde trafficking of IFT-1, IFT-B and GPCRs. Negatively modulates the SHH signal transduction.
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asphyxiating thoracic dystrophy 4	DIS95DFH	Definitive	Autosomal recessive	[1]
Nephronophthisis 12	DIS9KCZY	Definitive	Autosomal recessive	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[3]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[4]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Cystic kidney disease	DISRT1LM	Strong	CausalMutation	[5]
Drug dependence	DIS9IXRC	Strong	Biomarker	[6]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[4]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[5]
Interstitial nephritis	DISKQGND	Strong	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Myopia	DISK5S60	Strong	Genetic Variation	[5]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[4]
Substance abuse	DIS327VW	Strong	Biomarker	[6]
Substance dependence	DISDRAAR	Strong	Biomarker	[6]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[8]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[5]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[9]
Nephronophthisis 2	DIS5Y5KV	Supportive	Autosomal recessive	[9]

2 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 Tetratricopeptide repeat protein 21B (TTC21B).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Tetratricopeptide repeat protein 21B (TTC21B).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. doi: 10.1136/jmedgenet-2012-101282.
• [4] Mutations in TTC21B cause different phenotypes in two childhood cases in China.Nephrology (Carlton). 2018 Apr;23(4):371-376. doi: 10.1111/nep.13008.
• [5] Contribution of the TTC21B gene to glomerular and cystic kidney diseases.Nephrol Dial Transplant. 2017 Jan 1;32(1):151-156. doi: 10.1093/ndt/gfv453.
• [6] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [7] A novel adamantane thiadiazole derivative induces mitochondria-mediated apoptosis in lung carcinoma cell line.Bioorg Med Chem. 2017 Jan 1;25(1):241-253. doi: 10.1016/j.bmc.2016.10.040. Epub 2016 Nov 5.
• [8] Gpr63 is a modifier of microcephaly in Ttc21b mouse mutants.PLoS Genet. 2019 Nov 15;15(11):e1008467. doi: 10.1371/journal.pgen.1008467. eCollection 2019 Nov.
• [9] TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189-96. doi: 10.1038/ng.756. Epub 2011 Jan 23.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.