Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT10T7CK)

• DOT Name: Regulating synaptic membrane exocytosis protein 1 (RIMS1)
• Synonyms: Rab-3-interacting molecule 1; RIM 1; Rab-3-interacting protein 2
• Gene Name: RIMS1
• Related Disease:
  Neurodevelopmental disorder
  Autism
  Bipolar depression
  Bipolar disorder
  Chronic recurrent multifocal osteomyelitis
  Cone-rod dystrophy 7
  Neoplasm
  Retinitis pigmentosa
  Cone-rod dystrophy
  Autism spectrum disorder
  Cone-rod dystrophy 2
  Disorder of orbital region
  Glaucoma/ocular hypertension
  Inherited retinal dystrophy
  Venous thromboembolism
• UniProt ID: RIMS1_HUMAN
• PDB ID: 2CSS
• Pfam ID: PF00168 ; PF00595
• Sequence:
  MSSAVGPRGPRPPTVPPPMQELPDLSHLTEEERNIIMAVMDRQKEEEEKEEAMLKCVVRD
  MAKPAACKTPRNAENQPHQPSPRLHQQFESYKEQVRKIGEEARRYQGEHKDDAPTCGICH
  KTKFADGCGHLCSYCRTKFCARCGGRVSLRSNNEDKVVMWVCNLCRKQQEILTKSGAWFF
  GSGPQQTSQDGTLSDTATGAGSEVPREKKARLQERSRSQTPLSTAAASSQDAAPPSAPPD
  RSKGAEPSQQALGPEQKQASSRSRSEPPRERKKTPGLSEQNGKGALKSERKRVPKTSAQP
  VEGAVEERERKERRESRRLEKGRSQDYPDTPEKRDEGKAADEEKQRKEEDYQTRYRSDPN
  LARYPVKPPPEEQQMRMHARVSRARHERRHSDVALPRTEAGAALPEGKAGKRAPAAARAS
  PPDSPRAYSAERTAETRAPGAKQLTNHSPPAPRHGPVPAEAPELKAQEPLRKQSRLDPSS
  AVLMRKAKREKVETMLRNDSLSSDQSESVRPSPPKPHRSKRGGKKRQMSVSSSEEEGVST
  PEYTSCEDVELESESVSEKGDLDYYWLDPATWHSRETSPISSHPVTWQPSKEGDRLIGRV
  ILNKRTTMPKDSGALLGLKVVGGKMTDLGRLGAFITKVKKGSLADVVGHLRAGDEVLEWN
  GKPLPGATNEEVYNIILESKSEPQVEIIVSRPIGDIPRIPESSHPPLESSSSSFESQKME
  RPSISVISPTSPGALKDAPQVLPGQLSVKLWYDKVGHQLIVNVLQATDLPARVDGRPRNP
  YVKMYFLPDRSDKSKRRTKTVKKILEPKWNQTFVYSHVHRRDFRERMLEITVWDQPRVQE
  EESEFLGEILIELETALLDDEPHWYKLQTHDESSLPLPQPSPFMPRRHIHGESSSKKLQR
  SQRISDSDISDYEVDDGIGVVPPVGYRSSARESKSTTLTVPEQQRTTHHRSRSVSPHRGN
  DQGKPRSRLPNVPLQRSLDEIHPTRRSRSPTRHHDASRSPVDHRTRDVDSQYLSEQDSEL
  LMLPRAKRGRSAECLHTTRHLVRHYKTLPPKMPLLQSSSHWNIYSSILPAHTKTKSVTRQ
  DISLHHECFNSTVLRFTDEILVSELQPFLDRARSASTNCLRPDTSLHSPERERGRWSPSL
  DRRRPPSPRIQIQHASPENDRHSRKSERSSIQKQTRKGTASDAERVLPTCLSRRGHAAPR
  ATDQPVIRGKHPARSRSSEHSSIRTLCSMHHLVPGGSAPPSPLLTRMHRQRSPTQSPPAD
  TSFSSRRGRQLPQVPVRSGSIEQASLVVEERTRQMKMKVHRFKQTTGSGSSQELDREQYS
  KYNIHKDQYRSCDNVSAKSSDSDVSDVSAISRTSSASRLSSTSFMSEQSERPRGRISSFT
  PKMQGRRMGTSGRSIMKSTSVSGEMYTLEHNDGSQSDTAVGTVGAGGKKRRSSLSAKVVA
  IVSRRSRSTSQLSQTESGHKKLKSTIQRSTETGMAAEMRKMVRQPSRESTDGSINSYSSE
  GNLIFPGVRLGADSQFSDFLDGLGPAQLVGRQTLATPAMGDIQIGMEDKKGQLEVEVIRA
  RSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESPQGKVLQ
  VIVWGDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKLFPPSSLVDPTLTPLTRRASQSS
  LESSTGPPCIRS
• Function: Rab effector involved in exocytosis. May act as scaffold protein that regulates neurotransmitter release at the active zone. Essential for maintaining normal probability of neurotransmitter release and for regulating release during short-term synaptic plasticity. Plays a role in dendrite formation by melanocytes.
• Tissue Specificity: Expressed in melanocytes . Detected in brain and retina .
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Retrograde endocan.binoid sig.ling (hsa04723)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Bipolar depression	DISA75FU	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Chronic recurrent multifocal osteomyelitis	DIST1OU2	Strong	Genetic Variation	[4]
Cone-rod dystrophy 7	DISVA5ZE	Strong	Autosomal dominant	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[4]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[7]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[8]
Cone-rod dystrophy 2	DISX2RWY	Limited	Genetic Variation	[9]
Disorder of orbital region	DISH0ECJ	Limited	Biomarker	[10]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[11]
Inherited retinal dystrophy	DISGGL77	Limited	Genetic Variation	[12]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulating synaptic membrane exocytosis protein 1 (RIMS1).	[22]

References

• [1] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [2] Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.
• [3] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [4] Retinitis pigmentosa and bilateral cystoid macular oedema in a patient heterozygous for the RIM1 mutation previously associated with cone-rod dystrophy 7.Ophthalmic Genet. 2017 Mar-Apr;38(2):178-182. doi: 10.1080/13816810.2016.1183215. Epub 2016 May 13.
• [5] RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature. 2002 Jan 17;415(6869):321-6. doi: 10.1038/415321a.
• [6] Dermal Sinus Tract of Lumbosacral Spine in Children: Patterns on Magnetic Resonance Imaging and Scoring System.Cureus. 2017 Dec 4;9(12):e1906. doi: 10.7759/cureus.1906.
• [7] Genomic organisation and alternative splicing of human RIM1, a gene implicated in autosomal dominant cone-rod dystrophy (CORD7). Genomics. 2003 Mar;81(3):304-14. doi: 10.1016/s0888-7543(03)00010-7.
• [8] De novo gene disruptions in children on the autistic spectrum. Neuron. 2012 Apr 26;74(2):285-99. doi: 10.1016/j.neuron.2012.04.009.
• [9] Functional correlates of fundus autofluorescence abnormalities in patients with RPGR or RIMS1 mutations causing cone or cone rod dystrophy.Br J Ophthalmol. 2008 Jan;92(1):95-102. doi: 10.1136/bjo.2007.124008. Epub 2007 Oct 25.
• [10] Two heterozygous mutations identified in one Chinese patient with bilateral macular coloboma.Mol Med Rep. 2017 Sep;16(3):2505-2510. doi: 10.3892/mmr.2017.6887. Epub 2017 Jun 29.
• [11] Joint optic disc and cup boundary extraction from monocular fundus images.Comput Methods Programs Biomed. 2017 Aug;147:51-61. doi: 10.1016/j.cmpb.2017.06.004. Epub 2017 Jun 23.
• [12] Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation.J Med Genet. 2007 Jun;44(6):373-80. doi: 10.1136/jmg.2006.047407. Epub 2007 Jan 19.
• [13] Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism.Blood. 2017 Feb 9;129(6):783-790. doi: 10.1182/blood-2016-07-728840. Epub 2016 Dec 23.
• [14] 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.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] 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.
• [20] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.