Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYM3928)

• DOT Name: Rab GDP dissociation inhibitor alpha (GDI1)
• Synonyms: Rab GDI alpha; Guanosine diphosphate dissociation inhibitor 1; GDI-1; Oligophrenin-2; Protein XAP-4
• Gene Name: GDI1
• Related Disease:
  Intellectual disability, X-linked 41
  Ovarian neoplasm
  Amyotrophic lateral sclerosis type 1
  Choroideremia
  Familial amyotrophic lateral sclerosis
  Hermansky-Pudlak syndrome
  Intellectual disability, X-linked 1
  Intellectual disability, X-linked 100
  Intellectual disability, X-linked 19
  Intellectual disability, X-linked 30
  Intellectual disability, X-linked 45
  Intellectual disability, X-linked 46
  Intellectual disability, X-linked 49
  Intellectual disability, X-linked 58
  Intellectual disability, X-linked 63
  Intellectual disability, X-linked 72
  Intellectual disability, X-linked 9
  Intellectual disability, X-linked 90
  Intellectual disability, X-linked 91
  Intellectual disability, X-linked 93
  Intellectual disability, X-linked 95
  Intellectual disability, X-linked 96
  Intellectual disability, X-linked 97
  Intellectual disability, X-linked 99
  X-linked intellectual disability, Cantagrel type
  Autism spectrum disorder
  Neurodevelopmental disorder
  Non-syndromic X-linked intellectual disability
  X-linked intellectual disability
  Rett syndrome
• UniProt ID: GDIA_HUMAN
• Pfam ID: PF00996
• Sequence:
  MDEEYDVIVLGTGLTECILSGIMSVNGKKVLHMDRNPYYGGESSSITPLEELYKRFQLLE
  GPPESMGRGRDWNVDLIPKFLMANGQLVKMLLYTEVTRYLDFKVVEGSFVYKGGKIYKVP
  STETEALASNLMGMFEKRRFRKFLVFVANFDENDPKTFEGVDPQTTSMRDVYRKFDLGQD
  VIDFTGHALALYRTDDYLDQPCLETVNRIKLYSESLARYGKSPYLYPLYGLGELPQGFAR
  LSAIYGGTYMLNKPVDDIIMENGKVVGVKSEGEVARCKQLICDPSYIPDRVRKAGQVIRI
  ICILSHPIKNTNDANSCQIIIPQNQVNRKSDIYVCMISYAHNVAAQGKYIAIASTTVETT
  DPEKEVEPALELLEPIDQKFVAISDLYEPIDDGCESQVFCSCSYDATTHFETTCNDIKDI
  YKRMAGTAFDFENMKRKQNDVFGEAEQ
• Function: Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Promotes the dissociation of GDP-bound Rab proteins from the membrane and inhibits their activation. Promotes the dissociation of RAB1A, RAB3A, RAB5A and RAB10 from membranes.
• Tissue Specificity: Brain; predominant in neural and sensory tissues.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 41	DISMG202	Definitive	X-linked recessive	[1]
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[2]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[3]
Choroideremia	DISH4N9B	Strong	Genetic Variation	[4]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[3]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[4]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[5]
Intellectual disability, X-linked 100	DISX6CQ7	Strong	Biomarker	[6]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Biomarker	[6]
Intellectual disability, X-linked 30	DISOEQO6	Strong	Biomarker	[6]
Intellectual disability, X-linked 45	DIS1TLM2	Strong	Biomarker	[6]
Intellectual disability, X-linked 46	DISO2WQ2	Strong	Biomarker	[6]
Intellectual disability, X-linked 49	DISKDVXD	Strong	Biomarker	[6]
Intellectual disability, X-linked 58	DISRMLYX	Strong	Biomarker	[6]
Intellectual disability, X-linked 63	DISEBC1L	Strong	Biomarker	[6]
Intellectual disability, X-linked 72	DISQC206	Strong	Biomarker	[6]
Intellectual disability, X-linked 9	DISWT4BP	Strong	Biomarker	[6]
Intellectual disability, X-linked 90	DISLGNWQ	Strong	Biomarker	[6]
Intellectual disability, X-linked 91	DISVSHJD	Strong	Biomarker	[6]
Intellectual disability, X-linked 93	DIS5EFCO	Strong	Biomarker	[6]
Intellectual disability, X-linked 95	DIS1QZO7	Strong	Biomarker	[6]
Intellectual disability, X-linked 96	DIS14ZZ5	Strong	Biomarker	[6]
Intellectual disability, X-linked 97	DISQINN0	Strong	Biomarker	[6]
Intellectual disability, X-linked 99	DISW92UF	Strong	Biomarker	[6]
X-linked intellectual disability, Cantagrel type	DISP424V	Strong	Biomarker	[6]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[7]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[7]
Non-syndromic X-linked intellectual disability	DIS71AI3	Moderate	X-linked	[8]
X-linked intellectual disability	DISYJBY3	Disputed	Biomarker	[4]
Rett syndrome	DISGG5UV	Limited	Biomarker	[9]

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 Rab GDP dissociation inhibitor alpha (GDI1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rab GDP dissociation inhibitor alpha (GDI1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[17]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rab GDP dissociation inhibitor alpha (GDI1).	[22]

References

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• [2] Gene expression profiles with cDNA microarray reveal RhoGDI as a predictive marker for paclitaxel resistance in ovarian cancers.Oncol Rep. 2006 May;15(5):1265-71.
• [3] Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
• [4] Rab GTPases, intracellular traffic and disease.Trends Mol Med. 2002 Jan;8(1):23-30. doi: 10.1016/s1471-4914(01)02227-4.
• [5] Novel GDI1 mutation in a large family with nonsyndromic X-linked intellectual disability. Am J Med Genet A. 2011 Dec;155A(12):3067-70. doi: 10.1002/ajmg.a.34291. Epub 2011 Oct 14.
• [6] Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training.Hum Mol Genet. 2009 Jan 1;18(1):105-17. doi: 10.1093/hmg/ddn321. Epub 2008 Oct 1.
• [7] Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.Am J Hum Genet. 2014 May 1;94(5):677-94. doi: 10.1016/j.ajhg.2014.03.018. Epub 2014 Apr 24.
• [8] 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.
• [9] Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1).Am J Med Genet. 1998 Jun 30;78(2):169-72.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.