Details of Drug Off-Target (DOT)

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

• DOT Name: TBC1 domain family member 24 (TBC1D24)
• Gene Name: TBC1D24
• Related Disease:
  Alternating hemiplegia
  Alternating hemiplegia of childhood
  Autosomal recessive nonsyndromic hearing loss 86
  DOORS syndrome
  Familial infantile myoclonic epilepsy
  Nervous system disease
  Action myoclonus-renal failure syndrome
  Advanced cancer
  Autosomal dominant nonsyndromic hearing loss 65
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Childhood epilepsy with centrotemporal spikes
  Deafness
  Dentatorubral-pallidoluysian atrophy
  Dystonia
  Epilepsy
  Epilepsy syndrome
  Focal epilepsy
  Infantile epileptic-dyskinetic encephalopathy
  Movement disorder
  Neoplasm
  Pendred syndrome
  Perrault syndrome
  Progressive myoclonus epilepsy
  Sensorineural hearing loss disorder
  Unverricht-Lundborg syndrome
  West syndrome
  Autosomal dominant nonsyndromic hearing loss
  Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
  Hearing loss, autosomal recessive
  Malignant migrating partial seizures of infancy
  Progressive myoclonic epilepsy with dystonia
  Intellectual disability-sparse hair-brachydactyly syndrome
  Intellectual disability
  Neurodevelopmental disorder
  Nonsyndromic genetic hearing loss
  Parkinsonian disorder
• UniProt ID: TBC24_HUMAN
• Pfam ID: PF00566 ; PF07534
• Sequence:
  MDSPGYNCFVDKDKMDAAIQDLGPKELSCTELQELKQLARQGYWAQSHALRGKVYQRLIR
  DIPCRTVTPDASVYSDIVGKIVGKHSSSCLPLPEFVDNTQVPSYCLNARGEGAVRKILLC
  LANQFPDISFCPALPAVVALLLHYSIDEAECFEKACRILACNDPGRRLIDQSFLAFESSC
  MTFGDLVNKYCQAAHKLMVAVSEDVLQVYADWQRWLFGELPLCYFARVFDVFLVEGYKVL
  YRVALAILKFFHKVRAGQPLESDSVKQDIRTFVRDIAKTVSPEKLLEKAFAIRLFSRKEI
  QLLQMANEKALKQKGITVKQKSVSLSKRQFVHLAVHAENFRSEIVSVREMRDIWSWVPER
  FALCQPLLLFSSLQHGYSLARFYFQCEGHEPTLLLIKTTQKEVCGAYLSTDWSERNKFGG
  KLGFFGTGECFVFRLQPEVQRYEWVVIKHPELTKPPPLMAAEPTAPLSHSASSDPADRLS
  PFLAARHFNLPSKTESMFMAGGSDCLIVGGGGGQALYIDGDLNRGRTSHCDTFNNQPLCS
  ENFLIAAVEAWGFQDPDTQ
• Function: May act as a GTPase-activating protein for Rab family protein(s). Involved in neuronal projections development, probably through a negative modulation of ARF6 function. Involved in the regulation of synaptic vesicle trafficking.
• Tissue Specificity: Highest expression in brain.
• Reactome Pathway: TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alternating hemiplegia	DIS25HMJ	Definitive	Genetic Variation	[1]
Alternating hemiplegia of childhood	DISB31JE	Definitive	Genetic Variation	[1]
Autosomal recessive nonsyndromic hearing loss 86	DISL9HPW	Definitive	Autosomal recessive	[2]
DOORS syndrome	DISMR9ZU	Definitive	Autosomal recessive	[3]
Familial infantile myoclonic epilepsy	DISELJ0F	Definitive	Autosomal recessive	[4]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[5]
Action myoclonus-renal failure syndrome	DISI2BZN	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[7]
Autosomal dominant nonsyndromic hearing loss 65	DISEF6FN	Strong	Autosomal dominant	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[9]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[10]
Deafness	DISKCLH4	Strong	Genetic Variation	[11]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[6]
Dystonia	DISJLFGW	Strong	Genetic Variation	[12]
Epilepsy	DISBB28L	Strong	Genetic Variation	[13]
Epilepsy syndrome	DISLYXJ3	Strong	Genetic Variation	[14]
Focal epilepsy	DIS4LY5L	Strong	Genetic Variation	[15]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[16]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pendred syndrome	DISZ1MU8	Strong	Genetic Variation	[17]
Perrault syndrome	DISG2YOV	Strong	Genetic Variation	[17]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[14]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Genetic Variation	[6]
West syndrome	DISLIAU9	Strong	Genetic Variation	[18]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[11]
Focal epilepsy-intellectual disability-cerebro-cerebellar malformation	DISJ7OT6	Supportive	Autosomal recessive	[19]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[20]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[21]
Progressive myoclonic epilepsy with dystonia	DISB6JN5	Supportive	Autosomal recessive	[22]
Intellectual disability-sparse hair-brachydactyly syndrome	DISEB2FS	Disputed	Genetic Variation	[23]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[24]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[3]
Parkinsonian disorder	DISHGY45	Limited	CausalMutation	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of TBC1 domain family member 24 (TBC1D24).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of TBC1 domain family member 24 (TBC1D24).	[30]

11 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 TBC1 domain family member 24 (TBC1D24).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TBC1 domain family member 24 (TBC1D24).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TBC1 domain family member 24 (TBC1D24).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of TBC1 domain family member 24 (TBC1D24).	[31]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of TBC1 domain family member 24 (TBC1D24).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of TBC1 domain family member 24 (TBC1D24).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of TBC1 domain family member 24 (TBC1D24).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of TBC1 domain family member 24 (TBC1D24).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TBC1 domain family member 24 (TBC1D24).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of TBC1 domain family member 24 (TBC1D24).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of TBC1 domain family member 24 (TBC1D24).	[37]

References

• [1] Alternating Hemiplegia and Epilepsia Partialis Continua: A new phenotype for a novel compound TBC1D24 mutation.Seizure. 2017 Apr;47:71-73. doi: 10.1016/j.seizure.2017.03.003. Epub 2017 Mar 6.
• [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] 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] A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet. 2010 Sep 10;87(3):371-5. doi: 10.1016/j.ajhg.2010.08.001.
• [5] The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons.Hum Mol Genet. 2019 Feb 15;28(4):584-597. doi: 10.1093/hmg/ddy370.
• [6] A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.
• [7] Downregulation of TBC1 Domain Family Member 24 (BC1D24) Inhibits Breast Carcinoma Growth via IGF1R/PI3K/AKT Pathway.Med Sci Monit. 2018 Jun 12;24:3987-3996. doi: 10.12659/MSM.906736.
• [8] TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat. 2014 Jul;35(7):819-23. doi: 10.1002/humu.22557. Epub 2014 May 6.
• [9] Novel TBC1D24 Mutations in a Case of Nonconvulsive Status Epilepticus.Front Neurol. 2018 Jul 31;9:623. doi: 10.3389/fneur.2018.00623. eCollection 2018.
• [10] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [11] A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum Mutat. 2014 Jul;35(7):814-8. doi: 10.1002/humu.22558. Epub 2014 May 6.
• [12] TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model.Brain. 2019 Aug 1;142(8):2319-2335. doi: 10.1093/brain/awz175.
• [13] TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons.Cell Death Differ. 2019 Nov;26(11):2464-2478. doi: 10.1038/s41418-019-0313-x. Epub 2019 Mar 11.
• [14] Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations.Eur J Paediatr Neurol. 2015 Mar;19(2):251-6. doi: 10.1016/j.ejpn.2014.12.011. Epub 2014 Dec 20.
• [15] Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy.Epileptic Disord. 2016 Sep 1;18(3):324-8. doi: 10.1684/epd.2016.0849.
• [16] The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.Hum Mol Genet. 2019 May 1;28(9):1530-1547. doi: 10.1093/hmg/ddy445.
• [17] Unresolved questions regarding human hereditary deafness.Oral Dis. 2017 Jul;23(5):551-558. doi: 10.1111/odi.12516. Epub 2016 Jul 11.
• [18] The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 2014 Jan;13(1):44-58. doi: 10.1016/S1474-4422(13)70265-5. Epub 2013 Nov 29.
• [19] TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation. Epilepsy Res. 2013 Jul;105(1-2):240-4. doi: 10.1016/j.eplepsyres.2013.02.005. Epub 2013 Mar 19.
• [20] Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am J Hum Genet. 2014 Jan 2;94(1):144-52. doi: 10.1016/j.ajhg.2013.12.004.
• [21] Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat. 2013 Jun;34(6):869-72. doi: 10.1002/humu.22318. Epub 2013 Apr 12.
• [22] Early-onset progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J Neurogenet. 2010 Dec;24(4):207-15. doi: 10.3109/01677063.2010.514368.
• [23] Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):241-51. doi: 10.1002/ajmg.c.31415. Epub 2014 Aug 28.
• [24] A case of early-onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy.Am J Med Genet A. 2019 Apr;179(4):645-649. doi: 10.1002/ajmg.a.61056. Epub 2019 Jan 24.
• [25] Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations.Am J Med Genet A. 2016 Dec;170(12):3207-3214. doi: 10.1002/ajmg.a.37933. Epub 2016 Aug 19.
• [26] 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.
• [27] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [28] 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.
• [29] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [30] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [31] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [32] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [33] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [34] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [35] 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.
• [36] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [37] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.