Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJMMX9K)

• DOT Name: Neurogenic differentiation factor 2 (NEUROD2)
• Synonyms: NeuroD2; Class A basic helix-loop-helix protein 1; bHLHa1; NeuroD-related factor; NDRF
• Gene Name: NEUROD2
• Related Disease:
  Epileptic encephalopathy
  Developmental and epileptic encephalopathy, 72
  Infantile epileptic-dyskinetic encephalopathy
  Medulloblastoma
  Neoplasm
  Primitive neuroectodermal tumor
  Anxiety
  Anxiety disorder
  Isolated congenital microcephaly
  Infantile spasm
  Schizoaffective disorder
  Schizophrenia
  Glioblastoma multiforme
• UniProt ID: NDF2_HUMAN
• Pfam ID: PF00010 ; PF12533
• Sequence:
  MLTRLFSEPGLLSDVPKFASWGDGEDDEPRSDKGDAPPPPPPAPGPGAPGPARAAKPVPL
  RGEEGTEATLAEVKEEGELGGEEEEEEEEEEGLDEAEGERPKKRGPKKRKMTKARLERSK
  LRRQKANARERNRMHDLNAALDNLRKVVPCYSKTQKLSKIETLRLAKNYIWALSEILRSG
  KRPDLVSYVQTLCKGLSQPTTNLVAGCLQLNSRNFLTEQGADGAGRFHGSGGPFAMHPYP
  YPCSRLAGAQCQAAGGLGGGAAHALRTHGYCAAYETLYAAAGGGGASPDYNSSEYEGPLS
  PPLCLNGNFSLKQDSSPDHEKSYHYSMHYSALPGSRPTGHGLVFGSSAVRGGVHSENLLS
  YDMHLHHDRGPMYEELNAFFHN
• Function: Transcriptional regulator implicated in neuronal determination. Mediates calcium-dependent transcription activation by binding to E box-containing promoter. Critical factor essential for the repression of the genetic program for neuronal differentiation; prevents the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. Induces transcription of ZEB1, which in turn represses neuronal differentiation by down-regulating REST expression. Plays a role in the establishment and maturation of thalamocortical connections; involved in the segregation of thalamic afferents into distinct barrel domains within layer VI of the somatosensory cortex. Involved in the development of the cerebellar and hippocampal granular neurons, neurons in the basolateral nucleus of amygdala and the hypothalamic-pituitary axis. Associates with chromatin to the DPYSL3 E box-containing promoter.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epileptic encephalopathy	DISZOCA3	Definitive	GermlineCausalMutation	[1]
Developmental and epileptic encephalopathy, 72	DISMU5LP	Strong	Autosomal dominant	[2]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[1]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Altered Expression	[3]
Anxiety	DISIJDBA	moderate	Altered Expression	[5]
Anxiety disorder	DISBI2BT	moderate	Altered Expression	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[6]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[1]
Schizoaffective disorder	DISLBW6B	Disputed	Biomarker	[7]
Schizophrenia	DISSRV2N	Disputed	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Neurogenic differentiation factor 2 (NEUROD2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neurogenic differentiation factor 2 (NEUROD2).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neurogenic differentiation factor 2 (NEUROD2).	[11]

1 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 Neurogenic differentiation factor 2 (NEUROD2).	[9]

References

• [1] De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy. J Med Genet. 2019 Feb;56(2):113-122. doi: 10.1136/jmedgenet-2018-105322. Epub 2018 Oct 15.
• [2] Regulation of thalamocortical patterning and synaptic maturation by NeuroD2. Neuron. 2006 Mar 2;49(5):683-95. doi: 10.1016/j.neuron.2006.01.031.
• [3] Expression of neurogenic basic helix-loop-helix genes in primitive neuroectodermal tumors.Cancer Res. 1997 Aug 15;57(16):3526-31.
• [4] p53 and miR-210 regulated NeuroD2, a neuronal basic helix-loop-helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment.Int J Cancer. 2018 May 1;142(9):1817-1828. doi: 10.1002/ijc.31209. Epub 2017 Dec 23.
• [5] Lack of association between SNPs in the NEUROD2 gene and alcohol dependence in a German patient sample.Psychiatry Res. 2011 May 15;187(1-2):220-3. doi: 10.1016/j.psychres.2010.08.031. Epub 2010 Sep 28.
• [6] Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities.Birth Defects Res A Clin Mol Teratol. 2015 Apr;103(4):235-42. doi: 10.1002/bdra.23321. Epub 2014 Sep 24.
• [7] Associations of NEUROD2 polymorphisms and change of cognitive dysfunctions in schizophrenia and schizoaffective disorder after eight weeks of antipsychotic treatment.Cogn Neuropsychiatry. 2017 Jul;22(4):280-297. doi: 10.1080/13546805.2017.1322502. Epub 2017 May 4.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.