Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWW3H0K)

• DOT Name: Dipeptidyl aminopeptidase-like protein 6 (DPP6)
• Synonyms: DPPX; Dipeptidyl aminopeptidase-related protein; Dipeptidyl peptidase 6; Dipeptidyl peptidase IV-like protein; Dipeptidyl peptidase VI; DPP VI
• Gene Name: DPP6
• Related Disease:
  Acute myelogenous leukaemia
  Amelogenesis imperfecta type 1G
  Amyotrophic lateral sclerosis-parkinsonism-dementia complex
  Azoospermia
  Cardiac disease
  Cerebellar ataxia
  Choreatic disease
  Chronic obstructive pulmonary disease
  Endometriosis
  Herpes simplex infection
  Huntington disease
  Hypertrophic cardiomyopathy
  Multiple sclerosis
  Narcolepsy
  Neurodevelopmental disorder
  Pancreatic cancer
  Sleep disorder
  Tardive dyskinesia
  Tourette syndrome
  Ventricular fibrillation
  Autism
  Dementia
  Frontotemporal dementia
  Intellectual disability
  Isolated congenital microcephaly
  Pick disease
  Autosomal dominant primary microcephaly
  Paroxysmal familial ventricular fibrillation
  Complex neurodevelopmental disorder
  Arrhythmia
  Asthma
  Autism spectrum disorder
  Intellectual disability, autosomal dominant 33
  Neuroblastoma
  Ventricular fibrillation, paroxysmal familial, 2
• UniProt ID: DPP6_HUMAN
• PDB ID: 1XFD; 7E87; 7E89; 7E8B; 7E8E; 7E8G; 7E8H; 7UKG
• Pfam ID: PF00930 ; PF00326
• Sequence:
  MASLYQRFTGKINTSRSFPAPPEASHLLGGQGPEEDGGAGAKPLGPRAQAAAPRERGGGG
  GGAGGRPRFQYQARSDGDEEDELVGSNPPQRNWKGIAIALLVILVICSLIVTSVILLTPA
  EDNSLSQKKKVTVEDLFSEDFKIHDPEAKWISDTEFIYREQKGTVRLWNVETNTSTVLIE
  GKKIESLRAIRYEISPDREYALFSYNVEPIYQHSYTGYYVLSKIPHGDPQSLDPPEVSNA
  KLQYAGWGPKGQQLIFIFENNIYYCAHVGKQAIRVVSTGKEGVIYNGLSDWLYEEEILKT
  HIAHWWSPDGTRLAYAAINDSRVPIMELPTYTGSIYPTVKPYHYPKAGSENPSISLHVIG
  LNGPTHDLEMMPPDDPRMREYYITMVKWATSTKVAVTWLNRAQNVSILTLCDATTGVCTK
  KHEDESEAWLHRQNEEPVFSKDGRKFFFIRAIPQGGRGKFYHITVSSSQPNSSNDNIQSI
  TSGDWDVTKILAYDEKGNKIYFLSTEDLPRRRQLYSANTVGNFNRQCLSCDLVENCTYFS
  ASFSHSMDFFLLKCEGPGVPMVTVHNTTDKKKMFDLETNEHVKKAINDRQMPKVEYRDIE
  IDDYNLPMQILKPATFTDTTHYPLLLVVDGTPGSQSVAEKFEVSWETVMVSSHGAVVVKC
  DGRGSGFQGTKLLHEVRRRLGLLEEKDQMEAVRTMLKEQYIDRTRVAVFGKDYGGYLSTY
  ILPAKGENQGQTFTCGSALSPITDFKLYASAFSERYLGLHGLDNRAYEMTKVAHRVSALE
  EQQFLIIHPTADEKIHFQHTAELITQLIRGKANYSLQIYPDESHYFTSSSLKQHLYRSII
  NFFVECFRIQDKLLTVTAKEDEEED
• Function: Promotes cell surface expression of the potassium channel KCND2. Modulates the activity and gating characteristics of the potassium channel KCND2. Has no dipeptidyl aminopeptidase activity.
• Tissue Specificity: Expressed predominantly in brain.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Amelogenesis imperfecta type 1G	DISS8U5Q	Strong	Genetic Variation	[2]
Amyotrophic lateral sclerosis-parkinsonism-dementia complex	DISTHQI1	Strong	Biomarker	[3]
Azoospermia	DIS94181	Strong	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[6]
Choreatic disease	DISH8K3M	Strong	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[7]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[8]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[9]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[10]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[11]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[12]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[14]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[6]
Tardive dyskinesia	DISKA5RC	Strong	Biomarker	[15]
Tourette syndrome	DISX9D54	Strong	Biomarker	[16]
Ventricular fibrillation	DIS7IN76	Strong	Genetic Variation	[17]
Autism	DISV4V1Z	moderate	Biomarker	[18]
Dementia	DISXL1WY	moderate	Biomarker	[19]
Frontotemporal dementia	DISKYHXL	moderate	Genetic Variation	[19]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[20]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[20]
Pick disease	DISP6X50	moderate	Genetic Variation	[19]
Autosomal dominant primary microcephaly	DIS7WS7S	Supportive	Autosomal dominant	[20]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Supportive	Autosomal dominant	[21]
Complex neurodevelopmental disorder	DISB9AFI	Disputed	Autosomal dominant	[22]
Arrhythmia	DISFF2NI	Limited	Biomarker	[23]
Asthma	DISW9QNS	Limited	Genetic Variation	[24]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[25]
Intellectual disability, autosomal dominant 33	DIS6CBUY	Limited	Unknown	[20]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[26]
Ventricular fibrillation, paroxysmal familial, 2	DISKUUDE	Limited	Autosomal dominant	[27]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gentamicin	DMKINJO	Approved	Dipeptidyl aminopeptidase-like protein 6 (DPP6) increases the Renal function abnormal ADR of Gentamicin.	[34]

5 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 Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[28]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[30]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dipeptidyl aminopeptidase-like protein 6 (DPP6).	[33]

References

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• [2] A novel DPP6 variant in Chinese families causes early repolarization syndrome.Exp Cell Res. 2019 Nov 1;384(1):111561. doi: 10.1016/j.yexcr.2019.111561. Epub 2019 Aug 30.
• [3] Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.Nat Genet. 2008 Jan;40(1):29-31. doi: 10.1038/ng.2007.52. Epub 2007 Dec 16.
• [4] Mapping breakpoints of a familial chromosome insertion (18,7) (q22.1; q36.2q21.11) to DPP6 and CACNA2D1 genes in an azoospermic male.Gene. 2014 Aug 15;547(1):43-9. doi: 10.1016/j.gene.2014.06.007. Epub 2014 Jun 14.
• [5] A novel mutation of dipeptidyl aminopeptidase-like protein-6 in a family with suspicious idiopathic ventricular fibrillation.QJM. 2018 Jun 1;111(6):373-377. doi: 10.1093/qjmed/hcy033.
• [6] Antibody-associated CNS syndromes without signs of inflammation in the elderly.Neurology. 2017 Oct 3;89(14):1471-1475. doi: 10.1212/WNL.0000000000004541. Epub 2017 Sep 6.
• [7] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [8] Endometriosis is associated with rare copy number variants.PLoS One. 2014 Aug 1;9(8):e103968. doi: 10.1371/journal.pone.0103968. eCollection 2014.
• [9] Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells.Genome Res. 2000 Jul;10(7):1043-50. doi: 10.1101/gr.10.7.1043.
• [10] Genetics of sudden cardiac death syndromes.Curr Opin Cardiol. 2011 May;26(3):196-203. doi: 10.1097/HCO.0b013e3283459893.
• [11] Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans.Neurosci Lett. 2012 Nov 21;530(2):155-60. doi: 10.1016/j.neulet.2012.10.008. Epub 2012 Oct 13.
• [12] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [13] Gonadal mosaicism of large terminal de novo duplication and deletion in siblings with variable intellectual disability phenotypes.Mol Genet Genomic Med. 2019 Oct;7(10):e00954. doi: 10.1002/mgg3.954. Epub 2019 Sep 1.
• [14] Genome-wide association study of pancreatic cancer in Japanese population.PLoS One. 2010 Jul 29;5(7):e11824. doi: 10.1371/journal.pone.0011824.
• [15] New findings in pharmacogenetics of schizophrenia.Curr Opin Psychiatry. 2018 May;31(3):200-212. doi: 10.1097/YCO.0000000000000417.
• [16] DPP6 gene disruption in a family with Gilles de la Tourette syndrome.Neurogenetics. 2014 Oct;15(4):237-42. doi: 10.1007/s10048-014-0418-9. Epub 2014 Aug 17.
• [17] Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.J Am Heart Assoc. 2015 May 26;4(5):e001762. doi: 10.1161/JAHA.114.001762.
• [18] Implication of LRRC4C and DPP6 in neurodevelopmental disorders.Am J Med Genet A. 2017 Feb;173(2):395-406. doi: 10.1002/ajmg.a.38021. Epub 2016 Oct 19.
• [19] Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.Acta Neuropathol. 2019 Jun;137(6):901-918. doi: 10.1007/s00401-019-01976-3. Epub 2019 Mar 14.
• [20] Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation. Eur J Med Genet. 2013 Sep;56(9):484-9. doi: 10.1016/j.ejmg.2013.06.008. Epub 2013 Jul 5.
• [21] Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation. Am J Hum Genet. 2009 Apr;84(4):468-76. doi: 10.1016/j.ajhg.2009.02.009. Epub 2009 Mar 12.
• [22] 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.
• [23] Emerging Roles of Neuronal Ca(2+) Sensor-1 in Cardiac and Neuronal Tissues: A Mini Review.Front Mol Neurosci. 2019 Mar 4;12:56. doi: 10.3389/fnmol.2019.00056. eCollection 2019.
• [24] Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.J Allergy Clin Immunol. 2015 Nov;136(5):1240-6.e1-8. doi: 10.1016/j.jaci.2015.04.014. Epub 2015 May 27.
• [25] Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance.Gene. 2016 Dec 31;595(2):131-141. doi: 10.1016/j.gene.2016.09.027. Epub 2016 Sep 17.
• [26] A nanobody-based tracer targeting DPP6 for non-invasive imaging of human pancreatic endocrine cells.Sci Rep. 2017 Nov 9;7(1):15130. doi: 10.1038/s41598-017-15417-2.
• [27] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [28] 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.
• [29] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [30] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.