Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYFRM4Q)

• DOT Name: IQ motif and SEC7 domain-containing protein 2 (IQSEC2)
• Gene Name: IQSEC2
• Related Disease:
  Attention deficit hyperactivity disorder
  Intellectual disability, X-linked 1
  X-linked complex neurodevelopmental disorder
  Aicardi syndrome
  Autism spectrum disorder
  Charcot marie tooth disease
  Epilepsy
  Gram-positive bacterial infection
  Nervous system disease
  Neurodevelopmental disorder
  Smith-Magenis syndrome
  X-linked intellectual disability
  Intellectual disability
  Non-syndromic X-linked intellectual disability
  Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome
  Autism
  Glioma
  Rett syndrome
• UniProt ID: IQEC2_HUMAN
• PDB ID: 6FAE
• Pfam ID: PF16453 ; PF01369
• Sequence:
  MEAGSGPPGGPGSESPNRAVEYLLELNNIIESQQQLLETQRRRIEELEGQLDQLTQENRD
  LREESQLHRGELHRDPHGARDSPGRESQYQNLRETQFHHRELRESQFHQAARDVGYPNRE
  GAYQNREAVYRDKERDASYPLQDTTGYTARERDVAQCHLHHENPALGRERGGREAGPAHP
  GREKEAGYSAAVGVGPRPPRERGQLSRGASRSSSPGAGGGHSTSTSTSPATTLQRKSDGE
  NSRTVSVEGDAPGSDLSTAVDSPGSQPPYRLSQLPPSSSHMGGPPAGVGLPWAQRARLQP
  ASVALRKQEEEEIKRSKALSDSYELSTDLQDKKVEMLERKYGGSFLSRRAARTIQTAFRQ
  YRMNKNFERLRSSASESRMSRRIILSNMRMQFSFEEYEKAQNPAYFEGKPASLDEGAMAG
  ARSHRLERGLPYGGSCGGGIDGGGSSVTTSGEFSNDITELEDSFSKQVKSLAESIDEALN
  CHPSGPMSEEPGSAQLEKRESKEQQEDSSATSFSDLPLYLDDTVPQQSPERLPSTEPPPQ
  GRPEFWAPAPLPPVPPPVPSGTREDGSREEGTRRGPGCLECRDFRLRAAHLPLLTIEPPS
  DSSVDLSDRSDRGSVHRQLVYEADGCSPHGTLKHKGPPGRAPIPHRHYPAPEGPAPAPPG
  PLPPAPNSGTGPSGVAGGRRLGKCEAAGENSDGGDNESLESSSNSNETINCSSGSSSRDS
  LREPPATGLCKQTYQRETRHSWDSPAFNNDVVQRRHYRIGLNLFNKKPEKGIQYLIERGF
  LSDTPVGVAHFILERKGLSRQMIGEFLGNRQKQFNRDVLDCVVDEMDFSSMDLDDALRKF
  QSHIRVQGEAQKVERLIEAFSQRYCVCNPALVRQFRNPDTIFILAFAIILLNTDMYSPSV
  KAERKMKLDDFIKNLRGVDNGEDIPRDLLVGIYQRIQGRELRTNDDHVSQVQAVERMIVG
  KKPVLSLPHRRLVCCCQLYEVPDPNRPQRLGLHQREVFLFNDLLVVTKIFQKKKILVTYS
  FRQSFPLVEMHMQLFQNSYYQFGIKLLSAVPGGERKVLIIFNAPSLQDRLRFTSDLRESI
  AEVQEMEKYRVESELEKQKGMMRPNASQPGGAKDSVNGTMARSSLEDTYGAGDGLKRGAL
  SSSLRDLSDAGKRGRRNSVGSLDSTIEGSVISSPRPHQRMPPPPPPPPPEEYKSQRPVSN
  SSSFLGSLFGSKRGKGPFQMPPPPTGQASASSSSASSTHHHHHHHHHGHSHGGLGVLPDG
  QSKLQALHAQYCQGPGPAPPPYLPPQQPSLPPPPQQPPPLPQLGSIPPPPASAPPVGPHR
  HFHAHGPVPGPQHYTLGRPGRAPRRGAGGHPQFAPHGRHPLHQPTSPLPLYSPAPQHPPA
  HKQGPKHFIFSHHPQMMPAAGAAGGPGSRPPGGSYSHPHHPQSPLSPHSPIPPHPSYPPL
  PPPSPHTPHSPLPPTSPHGPLHASGPPGTANPPSANPKAKPSRISTVV
• Function: Is a guanine nucleotide exchange factor for the ARF GTP-binding proteins.
• Tissue Specificity: Expressed in brain, kidney and small intestine. Weakly expressed in placenta, pancreas, ovary, prostate and liver.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Genetic Variation	[1]
Intellectual disability, X-linked 1	DISET38E	Definitive	X-linked	[2]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[3]
Aicardi syndrome	DISBQXZB	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Gram-positive bacterial infection	DISZ44JH	Strong	Biomarker	[7]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[8]
Smith-Magenis syndrome	DISG4G6X	Strong	Genetic Variation	[9]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[2]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[6]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[10]
Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome	DISHEK6W	Supportive	X-linked	[11]
Autism	DISV4V1Z	Disputed	Biomarker	[12]
Glioma	DIS5RPEH	Limited	Biomarker	[13]
Rett syndrome	DISGG5UV	Limited	Genetic Variation	[14]

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 IQ motif and SEC7 domain-containing protein 2 (IQSEC2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of IQ motif and SEC7 domain-containing protein 2 (IQSEC2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of IQ motif and SEC7 domain-containing protein 2 (IQSEC2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of IQ motif and SEC7 domain-containing protein 2 (IQSEC2).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of IQ motif and SEC7 domain-containing protein 2 (IQSEC2).	[18]

References

• [1] Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders.Eur J Hum Genet. 2016 Mar;24(3):373-80. doi: 10.1038/ejhg.2015.123. Epub 2015 Jun 10.
• [2] Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene. Eur J Med Genet. 2020 Mar;63(3):103735. doi: 10.1016/j.ejmg.2019.103735. Epub 2019 Aug 12.
• [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] Chromosomal mapping of the human M6 genes.Genomics. 1996 May 1;33(3):532-6. doi: 10.1006/geno.1996.0231.
• [5] Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.
• [6] An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors.Front Mol Neurosci. 2019 Feb 20;12:43. doi: 10.3389/fnmol.2019.00043. eCollection 2019.
• [7] Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects.Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02181-16. doi: 10.1128/AAC.02181-16. Print 2017 Apr.
• [8] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [9] Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants. Hum Genet. 2017 Apr;136(4):409-420. doi: 10.1007/s00439-017-1767-x. Epub 2017 Feb 17.
• [10] Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet. 2010 Jun;42(6):486-8. doi: 10.1038/ng.588. Epub 2010 May 16.
• [11] Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability. Eur J Hum Genet. 2014 Feb;22(2):289-92. doi: 10.1038/ejhg.2013.113. Epub 2013 May 15.
• [12] IQSEC2-Associated Intellectual Disability and Autism.Int J Mol Sci. 2019 Jun 21;20(12):3038. doi: 10.3390/ijms20123038.
• [13] Identification of a novel Bcl-2 related gene, BRAG-1, in human glioma.Oncogene. 1996 Mar 7;12(5):947-51.
• [14] Monogenic disorders that mimic the phenotype of Rett syndrome.Neurogenetics. 2018 Jan;19(1):41-47. doi: 10.1007/s10048-017-0535-3. Epub 2018 Jan 10.
• [15] 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.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.