Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1FLIW)

• DOT Name: Rho guanine nucleotide exchange factor 9 (ARHGEF9)
• Synonyms: Collybistin; PEM-2 homolog; Rac/Cdc42 guanine nucleotide exchange factor 9
• Gene Name: ARHGEF9
• Related Disease:
  Autism
  Autism spectrum disorder
  Developmental and epileptic encephalopathy, 8
  Epilepsy
  Focal epilepsy
  Fragile X syndrome
  Hepatitis C virus infection
  Neurodevelopmental disorder
  X-linked complex neurodevelopmental disorder
  X-linked intellectual disability
  Hyperekplexia
  Alopecia
  Anxiety
  Anxiety disorder
  Hepatocellular carcinoma
  Intellectual disability
  Pervasive developmental disorder
• UniProt ID: ARHG9_HUMAN
• PDB ID: 2YSQ
• Pfam ID: PF00169 ; PF00621 ; PF07653
• Sequence:
  MTLLITGDSIVSAEAVWDHVTMANRELAFKAGDVIKVLDASNKDWWWGQIDDEEGWFPAS
  FVRLWVNQEDEVEEGPSDVQNGHLDPNSDCLCLGRPLQNRDQMRANVINEIMSTERHYIK
  HLKDICEGYLKQCRKRRDMFSDEQLKVIFGNIEDIYRFQMGFVRDLEKQYNNDDPHLSEI
  GPCFLEHQDGFWIYSEYCNNHLDACMELSKLMKDSRYQHFFEACRLLQQMIDIAIDGFLL
  TPVQKICKYPLQLAELLKYTAQDHSDYRYVAAALAVMRNVTQQINERKRRLENIDKIAQW
  QASVLDWEGEDILDRSSELIYTGEMAWIYQPYGRNQQRVFFLFDHQMVLCKKDLIRRDIL
  YYKGRIDMDKYEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAF
  REERKMVQEDEKIGFEISENQKRQAAMTVRKVPKQKGVNSARSVPPSYPPPQDPLNHGQY
  LVPDGIAQSQVFEFTEPKRSQSPFWQNFSRLTPFKK
• Function: Acts as a guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters.
• Tissue Specificity: Detected in brain. Detected at low levels in heart.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOQ GTPase cycle (R-HSA-9013406)
  GABA receptor activation (R-HSA-977443)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[1]
Developmental and epileptic encephalopathy, 8	DISMVLYC	Strong	X-linked	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Focal epilepsy	DIS4LY5L	Strong	Biomarker	[4]
Fragile X syndrome	DISE8W3A	Strong	Genetic Variation	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[7]
X-linked complex neurodevelopmental disorder	DISI3QE9	Moderate	X-linked	[8]
X-linked intellectual disability	DISYJBY3	moderate	Biomarker	[9]
Hyperekplexia	DISY3CG8	Disputed	Biomarker	[4]
Alopecia	DIS37HU4	Limited	Genetic Variation	[10]
Anxiety	DISIJDBA	Limited	Genetic Variation	[11]
Anxiety disorder	DISBI2BT	Limited	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[6]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[3]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor 9 (ARHGEF9).	[16]

References

• [1] Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation.Eur J Med Genet. 2019 Apr;62(4):239-242. doi: 10.1016/j.ejmg.2018.07.021. Epub 2018 Jul 23.
• [2] The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci. 2004 Jun 23;24(25):5816-26. doi: 10.1523/JNEUROSCI.1184-04.2004.
• [3] ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.Neurogenetics. 2018 Jan;19(1):9-16. doi: 10.1007/s10048-017-0528-2. Epub 2017 Nov 13.
• [4] The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures.J Neurol. 2017 Jul;264(7):1421-1425. doi: 10.1007/s00415-017-8539-3. Epub 2017 Jun 15.
• [5] ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.J Med Genet. 2008 Feb;45(2):100-5. doi: 10.1136/jmg.2007.052324. Epub 2007 Sep 24.
• [6] Identification of TAF1, SAT1, and ARHGEF9 as DNA methylation biomarkers for hepatocellular carcinoma.J Cell Physiol. 2020 Jan;235(1):611-618. doi: 10.1002/jcp.28999. Epub 2019 Jul 8.
• [7] Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.Hum Mol Genet. 2013 May 15;22(10):2055-66. doi: 10.1093/hmg/ddt056. Epub 2013 Feb 7.
• [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] Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses.J Cell Sci. 2011 Aug 15;124(Pt 16):2786-96. doi: 10.1242/jcs.086199.
• [10] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [11] A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.Hum Mutat. 2009 Jan;30(1):61-8. doi: 10.1002/humu.20814.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] 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.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.