Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB4JWN3)

• DOT Name: DmX-like protein 2 (DMXL2)
• Synonyms: Rabconnectin-3
• Gene Name: DMXL2
• Related Disease:
  Developmental and epileptic encephalopathy, 81
  Epileptic encephalopathy
  Infantile epileptic-dyskinetic encephalopathy
  Joubert syndrome
  Psoriasis
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive
  Stroke
  Autosomal dominant nonsyndromic hearing loss
  Infantile spasm
  Polyendocrine-polyneuropathy syndrome
  Intellectual disability
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Hearing loss, autosomal dominant 71
  Neurodevelopmental disorder
  Nonsyndromic genetic hearing loss
  Pervasive developmental disorder
• UniProt ID: DMXL2_HUMAN
• Pfam ID: PF12234 ; PF00400
• Sequence:
  MHLHQVLTGAVNPGDNCYSVGSVGDVPFTAYGSGCDIVILANDFECVQIIPGAKHGNIQV
  SCVECSNQQGRIAASYGNAVCIFEPLGINSHKRNCQLKCQWLKTGQFFLSSVTYNLAWDP
  QDNRLLTATDSIQLWAPPGDDILEEEEEIDNTVPPVLNDWKCVWQCKTSVSVHLMEWSPD
  GEYFATAGKDDCLLKVWYPMTGWKSSIIPQDHHEVKRRQSSTQFSFVYLAHPRAVTGFSW
  RKTSKYMPRGSVCNVLLTSCHDGVCRLWAETLLPEDCLLGEQICETTTSSIASSLSHAGR
  HKDRIQHALETIHHLKNLRKGQRRSSVLVTHAELMPDQTAMHEVQRHISHHANALCHFHI
  AASINPATDIPNVLVGTAFNVDDGNGGFVVHWLNNKEFHFTSSTEVFMHQLRKLSDKQVD
  HENDDADREDEEHSQEDRERGLHMKLDHDLSLDRESEAGTGSSEHEDGEREGSPRTYSRL
  SVPMPLPTVLLDRKIETLLTEWNKNPDMLFTIHPVDGTFLVWHVKYLDEYNPGIFRQVQV
  SFSSRIPVAFPSGDASSLSKNIMMYACINATKDSHHTLLHQEGMSVGSPHGSQPHSRSHS
  THMNILAPTVMMISKHIDGSLNQWAVTFADKSAFTTVLTVSHKFRYCGHRFHLNDLACHS
  VLPLLLTSSHHNALLTPELDCQWDSDNKLSRLMDPVKHIKGSSKQPLRNAATRTFHDPNA
  IYSELILWRVDPIGPLSYTGGVSELARINSLHTSAFSNVAWLPTLIPSYCLGTYCNSASA
  CFVASDGKNLRLYQAVVDARKLLDELSDPESSKLIGEVFNIVSQQSTARPGCIIELDAIT
  NQCGSNTQLLHVFQEDFIIGYKPHKEDMEKKETEIFFQPSQGYRPPPFSEKFFLVVIEKD
  SNNNSILHMWHLHLKSVQACLAKASEGASSESLLSVPGQKNVDSSPETSPSVSPMPHSSS
  IANLQTASKLILSSRLVYSQPLDLPESVEVIRATPSAGHLSSSSIYPVCLAPYLVVTTCS
  DNKVRFWKCCMEANPECNKSDEKEIYHWKRWPLMNDEGEDNSSTVSIVGRPVAVSCSYTG
  RLAVAYKQPIHHNGFVSKEFSMHVCIFECESTGGSEWVLEQTIHLDDLVKVGSVLDSRVS
  VDSNLFVYSKSDALLSKDRYLIPNIKHLVHLDWVSKEDGSHILTVGVGANIFMYGRLSGI
  VTEQTNSKDGVAVITLPLGGSIKQGVKSRWVLLRSIDLVSSVDGTPSLPVSLSWVRDGIL
  VVGMDCEMHVYAQWKHAVKFGDTEADSSNAEEAAMQDHSTFKSNMLARKSVVEGTAISDD
  VFCSPTVIQDGGLFEAAHVLSPTLPQYHPTQLLELMDLGKVRRAKAILSHLVKCIAGEVA
  IVRDPDAGEGTKRHLSRTISVSGSTAKETVTVGKDGTRDYTEIDSIPPLPLYALLAADQD
  TSYRISEESTKIPQSYEDQTVSQPEDQYSELFQIQDIPTDDIDLEPEKRENKSKVINLSQ
  YGPAYFGQEHARVLSSHLMHSSLPGLTRLEQMFLVALADTVATTSTELDESRDKSCSGRD
  TLDECGLRYLLAMRLHTCLLTSLPPLYRVQLLHQGVSTCHFAWAFHSEAEEELINMIPAI
  QRGDPQWSELRAMGIGWWVRNINTLRRCIEKVAKASFQRNNDALDAALFYLSMKKKAVVW
  GLFRSQHDEKMTTFFSHNFNEDRWRKAALKNAFSLLGKQRFEQSAAFFLLAGSLKDAIEV
  CLEKMEDIQLAMVIARLYESEFETSSTYISILNQKILGCQKDGSGFSCKRLHPDPFLRSL
  AYWVMKDYTRALDTLLEQTPKEDDEHQVIIKSCNPVAFSFYNYLRTHPLLIRRNLASPEG
  TLATLGLKTEKNFVDKINLIERKLFFTTANAHFKVGCPVLALEVLSKIPKVTKTSALSAK
  KDQPDFISHRMDDVPSHSKALSDGNGSSGIEWSNVTSSQYDWSQPIVKVDEEPLNLDWGE
  DHDSALDEEEDDAVGLVMKSTDAREKDKQSDQKASDPNMLLTPQEEDDPEGDTEVDVIAE
  QLKFRACLKILMTELRTLATGYEVDGGKLRFQLYNWLEKEIAALHEICNHESVIKEYSSK
  TYSKVESDLLDQEEMVDKPDIGSYERHQIERRRLQAKREHAERRKSWLQKNQDLLRVFLS
  YCSLHGAQGGGLASVRMELKFLLQESQQETTVKQLQSPLPLPTTLPLLSASIASTKTVIA
  NPVLYLNNHIHDILYTIVQMKTPPHPSIEDVKVHTLHSLAASLSASIYQALCDSHSYSQT
  EGNQFTGMAYQGLLLSDRRRLRTESIEEHATPNSSPAQWPGVSSLINLLSSAQDEDQPKL
  NILLCEAVVAVYLSLLIHALATNSSSELFRLAAHPLNNRMWAAVFGGGVKLVVKPRRQSE
  NISAPPVLSEDIDKHRRRFNMRMLVPGRPVKDATPPPVPAERPSYKEKFIPPELSMWDYF
  VAKPFLPLSDSGVIYDSDESIHSDEEDDAFFSDTQIQEHQDPNSYSWALLHLTMVKLALH
  NVKNFFPIAGLEFSELPVTSPLGIAVIKNLENWEQILQEKMDQFEGPPPNYINTYPTDLS
  VGAGPAILRNKAMLEPENTPFKSRDSSAFPVKRLWHFLVKQEVLQETFIRYIFTKKRKQS
  EVEADLGYPGGKAKVIHKESDMIMAFSVNKANCNEIVLASTHDVQELDVTSLLACQSYIW
  IGEEYDRESKSSDDVDYRGSTTTLYQPSATSYSASQVHPPSSLPWLGTGQTSTGASVLMK
  RNLHNVKRMTSHPVHQYYLTGAQDGSVRMFEWTRPQQLVCFRQAGNARVTRLYFNSQGNK
  CGVADGEGFLSIWQVNQTASNPKPYMSWQCHSKATSDFAFITSSSLVATSGHSNDNRNVC
  LWDTLISPGNSLIHGFTCHDHGATVLQYAPKQQLLISGGRKGHVCIFDIRQRQLIHTFQA
  HDSAIKALALDPYEEYFTTGSAEGNIKVWRLTGHGLIHSFKSEHAKQSIFRNIGAGVMQI
  DIIQGNRLFSCGADGTLKTRVLPNAFNIPNRILDIL
• Function: May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles. Plays a role in the brain as a key controller of neuronal and endocrine homeostatic processes.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 81	DISTIKTG	Strong	Autosomal recessive	[1]
Epileptic encephalopathy	DISZOCA3	Strong	Genetic Variation	[2]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[2]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[3]
Psoriasis	DIS59VMN	Strong	Biomarker	[4]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[2]
Hearing loss, autosomal recessive	DIS8G9R9	moderate	Biomarker	[5]
Stroke	DISX6UHX	moderate	Biomarker	[6]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[5]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[2]
Polyendocrine-polyneuropathy syndrome	DISYGT3D	Supportive	Autosomal recessive	[7]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[8]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[9]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]
Hearing loss, autosomal dominant 71	DISTYHRQ	Limited	Autosomal dominant	[11]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[9]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[12]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[9]

13 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 DmX-like protein 2 (DMXL2).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DmX-like protein 2 (DMXL2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DmX-like protein 2 (DMXL2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DmX-like protein 2 (DMXL2).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DmX-like protein 2 (DMXL2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DmX-like protein 2 (DMXL2).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DmX-like protein 2 (DMXL2).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DmX-like protein 2 (DMXL2).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of DmX-like protein 2 (DMXL2).	[21]
Selenium	DM25CGV	Approved	Selenium decreases the expression of DmX-like protein 2 (DMXL2).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DmX-like protein 2 (DMXL2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DmX-like protein 2 (DMXL2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DmX-like protein 2 (DMXL2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DmX-like protein 2 (DMXL2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DmX-like protein 2 (DMXL2).	[24]

References

• [1] Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x. Epub 2018 Sep 21.
• [2] Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course. Brain. 2019 Dec 1;142(12):3876-3891. doi: 10.1093/brain/awz326.
• [3] Mice with a conditional deletion of Talpid3 (KIAA0586)-a model for Joubert syndrome.J Pathol. 2019 Aug;248(4):396-408. doi: 10.1002/path.5271. Epub 2019 May 16.
• [4] Does imiquimod pretreatment optimize 308-nm excimer laser (UVB) therapy in psoriasis patients?.Photodermatol Photoimmunol Photomed. 2017 Jul;33(4):193-202. doi: 10.1111/phpp.12299. Epub 2017 Apr 20.
• [5] A dominant variant in DMXL2 is linked to nonsyndromic hearing loss. Genet Med. 2017 May;19(5):553-558. doi: 10.1038/gim.2016.142. Epub 2016 Sep 22.
• [6] Gene variants associated with ischemic stroke: the cardiovascular health study.Stroke. 2009 Feb;40(2):363-8. doi: 10.1161/STROKEAHA.108.521328. Epub 2008 Nov 20.
• [7] Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse. PLoS Biol. 2014 Sep 23;12(9):e1001952. doi: 10.1371/journal.pbio.1001952. eCollection 2014 Sep.
• [8] Dynamic Regulation of Hypothalamic DMXL2, KISS1, and RFRP Expression During Postnatal Development in Non-Human Primates.Mol Neurobiol. 2017 Dec;54(10):8447-8457. doi: 10.1007/s12035-016-0329-x. Epub 2016 Dec 12.
• [9] Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders.J Neurodev Disord. 2019 Feb 7;11(1):3. doi: 10.1186/s11689-019-9263-3.
• [10] DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation.Oncotarget. 2015 Sep 8;6(26):22467-79. doi: 10.18632/oncotarget.4164.
• [11] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [12] 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.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] 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.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] 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.
• [20] 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.
• [21] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [22] 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.
• [23] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.