Details of Drug Off-Target (DOT)

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

• DOT Name: Regulating synaptic membrane exocytosis protein 2 (RIMS2)
• Synonyms: Rab-3-interacting molecule 2; RIM 2; Rab-3-interacting protein 3
• Gene Name: RIMS2
• Related Disease:
  Acute leukaemia
  Cone-rod synaptic disorder syndrome, congenital nonprogressive
  Cone-rod synaptic disorder, congenital nonprogressive
  Hantavirus infection
  Hermansky-Pudlak syndrome
  Schizophrenia
  Small-cell lung cancer
  Neoplasm
• UniProt ID: RIMS2_HUMAN
• PDB ID: 1V27; 1WFG
• Pfam ID: PF00168 ; PF02318 ; PF00595
• Sequence:
  MSAPVGPRGRLAPIPAASQPPLQPEMPDLSHLTEEERKIILAVMDRQKKKVKEEHKPQLT
  QWFPFSGITELVNNVLQPQQKQQNEKEPQTKLHQQFEMYKEQVKKMGEESQQQQEQKGDA
  PTCGICHKTKFADGCGHNCSYCQTKFCARCGGRVSLRSNKVMWVCNLCRKQQEILTKSGA
  WFYNSGSNTPQQPDQKVLRGLRNEEAPQEKKPKLHEQTQFQGPSGDLSVPAVEKSRSHGL
  TRQHSIKNGSGVKHHIASDIASDRKRSPSVSRDQNRRYDQREEREEYSQYATSDTAMPRS
  PSDYADRRSQHEPQFYEDSDHLSYRDSNRRSHRHSKEYIVDDEDVESRDEYERQRREEEY
  QSRYRSDPNLARYPVKPQPYEEQMRIHAEVSRARHERRHSDVSLANADLEDSRISMLRMD
  RPSRQRSISERRAAMENQRSYSMERTREAQGPSSYAQRTTNHSPPTPRRSPLPIDRPDLR
  RTDSLRKQHHLDPSSAVRKTKREKMETMLRNDSLSSDQSESVRPPPPKPHKSKKGGKMRQ
  ISLSSSEEELASTPEYTSCDDVEIESESVSEKGDSQKGKRKTSEQAVLSDSNTRSERQKE
  MMYFGGHSLEEDLEWSEPQIKDSGVDTCSSTTLNEEHSHSDKHPVTWQPSKDGDRLIGRI
  LLNKRLKDGSVPRDSGAMLGLKVVGGKMTESGRLCAFITKVKKGSLADTVGHLRPGDEVL
  EWNGRLLQGATFEEVYNIILESKPEPQVELVVSRPIGDIPRIPDSTHAQLESSSSSFESQ
  KMDRPSISVTSPMSPGMLRDVPQFLSGQLSIKLWFDKVGHQLIVTILGAKDLPSREDGRP
  RNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYSPVHRREFRERMLEITLWDQAR
  VREEESEFLGEILIELETALLDDEPHWYKLQTHDVSSLPLPHPSPYMPRRQLHGESPTRR
  LQRSKRISDSEVSDYDCDDGIGVVSDYRHDGRDLQSSTLSVPEQVMSSNHCSPSGSPHRV
  DVIGRTRSWSPSVPPPQSRNVEQGLRGTRTMTGHYNTISRMDRHRVMDDHYSPDRDRDCE
  AADRQPYHRSRSTEQRPLLERTTTRSRSTERPDTNLMRSMPSLMTGRSAPPSPALSRSHP
  RTGSVQTSPSSTPVAGRRGRQLPQLPPKGTLDRKAGGKKLRSTVQRSTETGLAVEMRNWM
  TRQASRESTDGSMNSYSSEGNLIFPGVRLASDSQFSDFLDGLGPAQLVGRQTLATPAMGD
  IQVGMMDKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLE
  PLYQQLLSFEESPQGKVLQIIVWGDYGRMDHKSFMGVAQILLDELELSNMVIGWFKLFPP
  SSLVDPTLAPLTRRASQSSLESSTGPSYSRS
• Function: Rab effector involved in exocytosis. May act as scaffold protein. Plays a role in dendrite formation by melanocytes.
• Tissue Specificity: Widely expressed . Expressed in melanocytes . In fetal tissues, predominantly expressed in the brain . In the retina, expressed in the outer plexiform layer (at protein level) . In the cerebellum, expressed in Purkinje cells (at protein level) . In the pancreas, expressed in Langerhans islets (at protein level) .
• KEGG Pathway: Insulin secretion (hsa04911)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Cone-rod synaptic disorder syndrome, congenital nonprogressive	DISXMZGR	Strong	Autosomal recessive	[2]
Cone-rod synaptic disorder, congenital nonprogressive	DIS9ZCRA	Strong	Autosomal recessive	[3]
Hantavirus infection	DISZFTMH	Strong	Genetic Variation	[4]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[5]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]

6 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 Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[10]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Regulating synaptic membrane exocytosis protein 2 (RIMS2).	[13]

References

• [1] Biparental inheritance of chromosomal abnormalities in male twins with non-syndromic mental retardation.Eur J Med Genet. 2011 Jul-Aug;54(4):e383-8. doi: 10.1016/j.ejmg.2011.03.008. Epub 2011 Mar 21.
• [2] Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement. Am J Hum Genet. 2020 Jun 4;106(6):859-871. doi: 10.1016/j.ajhg.2020.04.018. Epub 2020 May 28.
• [3] Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement. Am J Hum Genet. 2020 Sep 3;107(3):580. doi: 10.1016/j.ajhg.2020.08.004.
• [4] rim2 (recombination-induced mutation 2) is a new allele of pearl and a mouse model of human Hermansky-Pudlak syndrome (HPS): genetic and physical mapping.Mamm Genome. 1998 Jan;9(1):2-7. doi: 10.1007/s003359900670.
• [5] Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: effects of antipsychotic drugs.J Psychiatr Res. 2009 Jan;43(3):282-90. doi: 10.1016/j.jpsychires.2008.04.001. Epub 2008 May 19.
• [6] Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.
• [7] Rearrangement of the p53 gene in human osteogenic sarcomas.Proc Natl Acad Sci U S A. 1987 Nov;84(21):7716-9. doi: 10.1073/pnas.84.21.7716.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.