Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL7PRMK)

• DOT Name: Cell adhesion molecule DSCAM (DSCAM)
• Synonyms: CHD2; Down syndrome cell adhesion molecule
• Gene Name: DSCAM
• Related Disease:
  Cerebral infarction
  Chronic renal failure
  Neurodevelopmental disorder
  Anxiety
  Autism
  Bipolar disorder
  Brain disease
  Charcot-Marie-Tooth disease type 1A
  Drug dependence
  Epilepsy
  Fragile X syndrome
  Major depressive disorder
  Substance abuse
  Substance dependence
  Temporal lobe epilepsy
  Autism spectrum disorder
  Congenital heart disease
  Hirschsprung disease
  Intellectual disability
• UniProt ID: DSCAM_HUMAN
• PDB ID: 6ZR7
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MWILALSLFQSFANVFSEDLHSSLYFVNASLQEVVFASTTGTLVPCPAAGIPPVTLRWYL
  ATGEEIYDVPGIRHVHPNGTLQIFPFPPSSFSTLIHDNTYYCTAENPSGKIRSQDVHIKA
  VLREPYTVRVEDQKTMRGNVAVFKCIIPSSVEAYITVVSWEKDTVSLVSGSRFLITSTGA
  LYIKDVQNEDGLYNYRCITRHRYTGETRQSNSARLFVSDPANSAPSILDGFDHRKAMAGQ
  RVELPCKALGHPEPDYRWLKDNMPLELSGRFQKTVTGLLIENIRPSDSGSYVCEVSNRYG
  TAKVIGRLYVKQPLKATISPRKVKSSVGSQVSLSCSVTGTEDQELSWYRNGEILNPGKNV
  RITGINHENLIMDHMVKSDGGAYQCFVRKDKLSAQDYVQVVLEDGTPKIISAFSEKVVSP
  AEPVSLMCNVKGTPLPTITWTLDDDPILKGGSHRISQMITSEGNVVSYLNISSSQVRDGG
  VYRCTANNSAGVVLYQARINVRGPASIRPMKNITAIAGRDTYIHCRVIGYPYYSIKWYKN
  SNLLPFNHRQVAFENNGTLKLSDVQKEVDEGEYTCNVLVQPQLSTSQSVHVTVKVPPFIQ
  PFEFPRFSIGQRVFIPCVVVSGDLPITITWQKDGRPIPGSLGVTIDNIDFTSSLRISNLS
  LMHNGNYTCIARNEAAAVEHQSQLIVRVPPKFVVQPRDQDGIYGKAVILNCSAEGYPVPT
  IVWKFSKGAGVPQFQPIALNGRIQVLSNGSLLIKHVVEEDSGYYLCKVSNDVGADVSKSM
  YLTVKIPAMITSYPNTTLATQGQKKEMSCTAHGEKPIIVRWEKEDRIINPEMARYLVSTK
  EVGEEVISTLQILPTVREDSGFFSCHAINSYGEDRGIIQLTVQEPPDPPEIEIKDVKART
  ITLRWTMGFDGNSPITGYDIECKNKSDSWDSAQRTKDVSPQLNSATIIDIHPSSTYSIRM
  YAKNRIGKSEPSNELTITADEAAPDGPPQEVHLEPISSQSIRVTWKAPKKHLQNGIIRGY
  QIGYREYSTGGNFQFNIISVDTSGDSEVYTLDNLNKFTQYGLVVQACNRAGTGPSSQEII
  TTTLEDVPSYPPENVQAIATSPESISISWSTLSKEALNGILQGFRVIYWANLMDGELGEI
  KNITTTQPSLELDGLEKYTNYSIQVLAFTRAGDGVRSEQIFTRTKEDVPGPPAGVKAAAA
  SASMVFVSWLPPLKLNGIIRKYTVFCSHPYPTVISEFEASPDSFSYRIPNLSRNRQYSVW
  VVAVTSAGRGNSSEIITVEPLAKAPARILTFSGTVTTPWMKDIVLPCKAVGDPSPAVKWM
  KDSNGTPSLVTIDGRRSIFSNGSFIIRTVKAEDSGYYSCIANNNWGSDEIILNLQVQVPP
  DQPRLTVSKTTSSSITLSWLPGDNGGSSIRGYILQYSEDNSEQWGSFPISPSERSYRLEN
  LKCGTWYKFTLTAQNGVGPGRISEIIEAKTLGKEPQFSKEQELFASINTTRVRLNLIGWN
  DGGCPITSFTLEYRPFGTTVWTTAQRTSLSKSYILYDLQEATWYELQMRVCNSAGCAEKQ
  ANFATLNYDGSTIPPLIKSVVQNEEGLTTNEGLKMLVTISCILVGVLLLFVLLLVVRRRR
  REQRLKRLRDAKSLAEMLMSKNTRTSDTLSKQQQTLRMHIDIPRAQLLIEERDTMETIDD
  RSTVLLTDADFGEAAKQKSLTVTHTVHYQSVSQATGPLVDVSDARPGTNPTTRRNAKAGP
  TARNRYASQWTLNRPHPTISAHTLTTDWRLPTPRAAGSVDKESDSYSVSPSQDTDRARSS
  MVSTESASSTYEELARAYEHAKMEEQLRHAKFTITECFISDTSSEQLTAGTNEYTDSLTS
  STPSESGICRFTASPPKPQDGGRVMNMAVPKAHRPGDLIHLPPYLRMDFLLNRGGPGTSR
  DLSLGQACLEPQKSRTLKRPTVLEPIPMEAASSASSTREGQSWQPGAVATLPQREGAELG
  QAAKMSSSQESLLDSRGHLKGNNPYAKSYTLV
• Function: Cell adhesion molecule that plays a role in neuronal self-avoidance. Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells. Mediates within retinal amacrine and ganglion cell subtypes both isoneuronal self-avoidance for creating an orderly dendritic arborization and heteroneuronal self-avoidance to maintain the mosaic spacing between amacrine and ganglion cell bodies. Receptor for netrin required for axon guidance independently of and in collaboration with the receptor DCC. Might also collaborate with UNC5C in NTN1-mediated axon repulsion independently of DCC. In spinal cord development plays a role in guiding commissural axons projection and pathfinding across the ventral midline to reach the floor plate upon ligand binding. Mediates intracellular signaling by stimulating the activation of MAPK8 and MAP kinase p38. Adhesion molecule that promotes lamina-specific synaptic connections in the retina: expressed in specific subsets of interneurons and retinal ganglion cells (RGCs) and promotes synaptic connectivity via homophilic interactions.
• Tissue Specificity: Primarily expressed in brain.
• Reactome Pathway: DSCAM interactions (R-HSA-376172)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral infarction	DISR1WNP	Definitive	Biomarker	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[2]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[3]
Anxiety	DISIJDBA	Strong	Genetic Variation	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Brain disease	DIS6ZC3X	Strong	Altered Expression	[7]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Strong	Genetic Variation	[8]
Drug dependence	DIS9IXRC	Strong	Biomarker	[9]
Epilepsy	DISBB28L	Strong	Altered Expression	[10]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[7]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Substance abuse	DIS327VW	Strong	Biomarker	[9]
Substance dependence	DISDRAAR	Strong	Biomarker	[9]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[10]
Autism spectrum disorder	DISXK8NV	Moderate	Autosomal dominant	[11]
Congenital heart disease	DISQBA23	Limited	Altered Expression	[12]
Hirschsprung disease	DISUUSM1	Limited	Genetic Variation	[13]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[14]

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 decreases the methylation of Cell adhesion molecule DSCAM (DSCAM).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cell adhesion molecule DSCAM (DSCAM).	[16]

References

• [1] Implication of "Down syndrome cell adhesion molecule" in the hippocampal neurogenesis of ischemic monkeys.Hippocampus. 2006;16(11):924-35. doi: 10.1002/hipo.20223.
• [2] Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.Front Genet. 2019 May 24;10:494. doi: 10.3389/fgene.2019.00494. eCollection 2019.
• [3] 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.
• [4] Genome-wide association study of co-occurring anxiety in major depression.World J Biol Psychiatry. 2013 Dec;14(8):611-21. doi: 10.3109/15622975.2013.782107. Epub 2013 Sep 19.
• [5] Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.Am J Hum Genet. 2016 Jan 7;98(1):58-74. doi: 10.1016/j.ajhg.2015.11.023. Epub 2015 Dec 31.
• [6] Association study between the Down syndrome cell adhesion molecule (DSCAM) gene and bipolar disorder.Psychiatr Genet. 2008 Feb;18(1):1-10. doi: 10.1097/YPG.0b013e3281ac238e.
• [7] Dysregulated Dscam levels act through Abelson tyrosine kinase to enlarge presynaptic arbors.Elife. 2015 May 19;4:e05196. doi: 10.7554/eLife.05196.
• [8] Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.J Neuromuscul Dis. 2019;6(2):201-211. doi: 10.3233/JND-190377.
• [9] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [10] Altered expression of Dscam in temporal lobe tissue from human and experimental animals.Synapse. 2011 Oct;65(10):975-82. doi: 10.1002/syn.20924. Epub 2011 Mar 28.
• [11] 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.
• [12] Refining chromosomal region critical for Down syndrome-related heart defects with a case of cryptic 21q22.2 duplication.Congenit Anom (Kyoto). 2005 Jun;45(2):62-4. doi: 10.1111/j.1741-4520.2005.00065.x.
• [13] Association between DSCAM polymorphisms and non-syndromic Hirschsprung disease in Chinese population.BMC Med Genet. 2018 Jul 13;19(1):116. doi: 10.1186/s12881-018-0637-2.
• [14] Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation.EMBO J. 2019 Mar 15;38(6):e99669. doi: 10.15252/embj.201899669. Epub 2019 Feb 11.
• [15] 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.
• [16] 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.