Details of Drug Off-Target (DOT)

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

• DOT Name: Tubulin-specific chaperone E (TBCE)
• Synonyms: Tubulin-folding cofactor E
• Gene Name: TBCE
• Related Disease:
  Hypoparathyroidism-retardation-dysmorphism syndrome
  Acute graft versus host disease
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Autoimmune polyendocrine syndrome type 1
  Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
  Fetal growth restriction
  Herpes simplex infection
  Hypoparathyroidism
  Intellectual disability
  Keratoconjunctivitis sicca
  Motor neurone disease
  Obesity
  Paroxysmal nocturnal haemoglobinuria
  Trichohepatoenteric syndrome
  Triple negative breast cancer
  Autosomal recessive Kenny-Caffey syndrome
  Isolated congenital microcephaly
  Advanced cancer
  Autosomal dominant Kenny-Caffey syndrome
  Bacterial infection
  Chronic graft versus host disease
  Distal hereditary motor neuropathy
  Encephalopathy, progressive, with amyotrophy and optic atrophy
  Kenny-Caffey syndrome
  Xerophthalmia
• UniProt ID: TBCE_HUMAN
• PDB ID: 4ICU; 4ICV
• Pfam ID: PF01302 ; PF14560
• Sequence:
  MSDTLTADVIGRRVEVNGEHATVRFAGVVPPVAGPWLGVEWDNPERGKHDGSHEGTVYFK
  CRHPTGGSFIRPNKVNFGTDFLTAIKNRYVLEDGPEEDRKEQIVTIGNKPVETIGFDSIM
  KQQSQLSKLQEVSLRNCAVSCAGEKGGVAEACPNIRKVDLSKNLLSSWDEVIHIADQLRH
  LEVLNVSENKLKFPSGSVLTGTLSVLKVLVLNQTGITWAEVLRCVAGCPGLEELYLESNN
  IFISERPTDVLQTVKLLDLSSNQLIDENQLYLIAHLPRLEQLILSDTGISSLHFPDAGIG
  CKTSMFPSLKYLVVNDNQISQWSFFNELEKLPSLRALSCLRNPLTKEDKEAETARLLIIA
  SIGQLKTLNKCEILPEERRRAELDYRKAFGNEWKQAGGHKDPEKNRLSEEFLTAHPRYQF
  LCLKYGAPEDWELKTQQPLMLKNQLLTLKIKYPHQLDQKVLEKQLPGSMTIQKVKGLLSR
  LLKVPVSDLLLSYESPKKPGREIELENDLKSLQFYSVENGDCLLVRW
• Function: Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation. Required for correct organization of microtubule cytoskeleton and mitotic splindle, and maintenance of the neuronal microtubule network.
• Reactome Pathway: Post-chaperonin tubulin folding pathway (R-HSA-389977)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypoparathyroidism-retardation-dysmorphism syndrome	DISZYT82	Definitive	Autosomal recessive	[1]
Acute graft versus host disease	DIS8KLVM	Strong	Genetic Variation	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	Strong	Biomarker	[4]
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	DISHPNJQ	Strong	Autosomal recessive	[5]
Fetal growth restriction	DIS5WEJ5	Strong	Genetic Variation	[6]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
Hypoparathyroidism	DISICS0V	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Keratoconjunctivitis sicca	DISNOENH	Strong	Genetic Variation	[10]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[11]
Obesity	DIS47Y1K	Strong	Genetic Variation	[12]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Biomarker	[2]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[13]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[14]
Autosomal recessive Kenny-Caffey syndrome	DISN3BL7	Moderate	Autosomal recessive	[15]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[16]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[17]
Autosomal dominant Kenny-Caffey syndrome	DISBSFV8	Limited	Biomarker	[1]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[1]
Chronic graft versus host disease	DIS1MM9J	Limited	Biomarker	[10]
Distal hereditary motor neuropathy	DISGS2ID	Limited	Genetic Variation	[18]
Encephalopathy, progressive, with amyotrophy and optic atrophy	DISJAE3C	Limited	Autosomal recessive	[15]
Kenny-Caffey syndrome	DISEL08B	Limited	Genetic Variation	[18]
Xerophthalmia	DIS5B72B	Limited	Genetic Variation	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Tubulin-specific chaperone E (TBCE) affects the response to substance of Fluorouracil.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tubulin-specific chaperone E (TBCE).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tubulin-specific chaperone E (TBCE).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tubulin-specific chaperone E (TBCE).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tubulin-specific chaperone E (TBCE).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tubulin-specific chaperone E (TBCE).	[23]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Tubulin-specific chaperone E (TBCE).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tubulin-specific chaperone E (TBCE).	[25]

References

• [1] Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet. 2002 Nov;32(3):448-52. doi: 10.1038/ng1012. Epub 2002 Oct 21.
• [2] Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria.Leuk Lymphoma. 2016;57(4):835-41. doi: 10.3109/10428194.2015.1068309. Epub 2016 Feb 24.
• [3] The superiority of haploidentical related stem cell transplantation over chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia in first complete remission.Blood. 2012 Jun 7;119(23):5584-90. doi: 10.1182/blood-2011-11-389809. Epub 2012 Apr 24.
• [4] Analysis of AP2S1, a calcium-sensing receptor regulator, in familial and sporadic isolated hypoparathyroidism.J Clin Endocrinol Metab. 2014 Mar;99(3):E469-73. doi: 10.1210/jc.2013-3136. Epub 2014 Jan 1.
• [5] Progesterone and oestradiol-17 beta in buffaloes showing gestational oestrus. Zentralbl Veterinarmed A. 1979 Aug;26(6):502-5. doi: 10.1111/j.1439-0442.1979.tb01624.x.
• [6] Ophthalmic features of hypoparathyroidism-retardation-dysmorphism.J AAPOS. 2007 Jun;11(3):288-90. doi: 10.1016/j.jaapos.2006.10.015. Epub 2007 Jan 25.
• [7] A host cell protein binds to a highly conserved sequence element (pac-2) within the cytomegalovirus a sequence.J Virol. 1989 Nov;63(11):4715-28. doi: 10.1128/JVI.63.11.4715-4728.1989.
• [8] Comprehensive next-generation sequencing analyses of hypoparathyroidism: identification of novel GCM2 mutations.J Clin Endocrinol Metab. 2014 Nov;99(11):E2421-8. doi: 10.1210/jc.2014-2174. Epub 2014 Aug 19.
• [9] A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2.J Bone Miner Res. 2014 Apr;29(4):992-8. doi: 10.1002/jbmr.2091.
• [10] Scleral lenses for severe chronic GvHD-related keratoconjunctivitis sicca: a retrospective study by the SFGM-TC.Bone Marrow Transplant. 2017 Jun;52(6):878-882. doi: 10.1038/bmt.2017.9. Epub 2017 Feb 20.
• [11] A missense mutation in Tbce causes progressive motor neuronopathy in mice.Nat Genet. 2002 Nov;32(3):443-7. doi: 10.1038/ng1016. Epub 2002 Oct 21.
• [12] Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.PLoS Genet. 2009 Jun;5(6):e1000508. doi: 10.1371/journal.pgen.1000508. Epub 2009 Jun 26.
• [13] Mutation in the TBCE gene is associated with hypoparathyroidism-retardation-dysmorphism syndrome featuring pituitary hormone deficiencies and hypoplasia of the anterior pituitary and the corpus callosum.J Clin Endocrinol Metab. 2009 Aug;94(8):2686-91. doi: 10.1210/jc.2008-2788. Epub 2009 Jun 2.
• [14] Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105.J Clin Oncol. 2015 Jun 10;33(17):1895-901. doi: 10.1200/JCO.2014.57.0085. Epub 2015 Apr 6.
• [15] 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.
• [16] A case of severe TBCE-negative hypoparathyroidism-retardation-dysmorphism syndrome: Case report and literature review.Am J Med Genet A. 2018 Aug;176(8):1768-1772. doi: 10.1002/ajmg.a.38851. Epub 2018 Jul 28.
• [17] New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.Curr Treat Options Oncol. 2016 Mar;17(3):12. doi: 10.1007/s11864-015-0378-9.
• [18] TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy.Am J Hum Genet. 2016 Oct 6;99(4):974-983. doi: 10.1016/j.ajhg.2016.08.006. Epub 2016 Sep 22.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [25] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.