Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCD8K5D)

• DOT Name: Seizure protein 6 homolog (SEZ6)
• Synonyms: SEZ-6; hSEZ-6
• Gene Name: SEZ6
• Related Disease:
  Alzheimer disease
  Epilepsy
  Plasma cell myeloma
  Niemann-Pick disease type C
  Mental disorder
• UniProt ID: SEZ6_HUMAN
• Pfam ID: PF00431 ; PF00084
• Sequence:
  MRPVALLLLPSLLALLAHGLSLEAPTVGKGQAPGIEETDGELTAAPTPEQPERGVHFVTT
  APTLKLLNHHPLLEEFLQEGLEKGDEELRPALPFQPDPPAPFTPSPLPRLANQDSRPVFT
  SPTPAMAAVPTQPQSKEGPWSPESESPMLRITAPLPPGPSMAVPTLGPGEIASTTPPSRA
  WTPTQEGPGDMGRPWVAEVVSQGAGIGIQGTITSSTASGDDEETTTTTTIITTTITTVQT
  PGPCSWNFSGPEGSLDSPTDLSSPTDVGLDCFFYISVYPGYGVEIKVQNISLREGETVTV
  EGLGGPDPLPLANQSFLLRGQVIRSPTHQAALRFQSLPPPAGPGTFHFHYQAYLLSCHFP
  RRPAYGDVTVTSLHPGGSARFHCATGYQLKGARHLTCLNATQPFWDSKEPVCIAACGGVI
  RNATTGRIVSPGFPGNYSNNLTCHWLLEAPEGQRLHLHFEKVSLAEDDDRLIIRNGDNVE
  APPVYDSYEVEYLPIEGLLSSGKHFFVELSTDSSGAAAGMALRYEAFQQGHCYEPFVKYG
  NFSSSTPTYPVGTTVEFSCDPGYTLEQGSIIIECVDPHDPQWNETEPACRAVCSGEITDS
  AGVVLSPNWPEPYGRGQDCIWGVHVEEDKRIMLDIRVLRIGPGDVLTFYDGDDLTARVLG
  QYSGPRSHFKLFTSMADVTIQFQSDPGTSVLGYQQGFVIHFFEVPRNDTCPELPEIPNGW
  KSPSQPELVHGTVVTYQCYPGYQVVGSSVLMCQWDLTWSEDLPSCQRVTSCHDPGDVEHS
  RRLISSPKFPVGATVQYICDQGFVLMGSSILTCHDRQAGSPKWSDRAPKCLLEQLKPCHG
  LSAPENGARSPEKQLHPAGATIHFSCAPGYVLKGQASIKCVPGHPSHWSDPPPICRAASL
  DGFYNSRSLDVAKAPAASSTLDAAHIAAAIFLPLVAMVLLVGGVYFYFSRLQGKSSLQLP
  RPRPRPYNRITIESAFDNPTYETGSLSFAGDERI
• Function: May play a role in cell-cell recognition and in neuronal membrane signaling. Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. Involved in the development of appropriate excitatory synaptic connectivity.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[3]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[4]
Mental disorder	DIS3J5R8	Limited	Altered Expression	[5]

9 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 Seizure protein 6 homolog (SEZ6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Seizure protein 6 homolog (SEZ6).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Seizure protein 6 homolog (SEZ6).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Seizure protein 6 homolog (SEZ6).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Seizure protein 6 homolog (SEZ6).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Seizure protein 6 homolog (SEZ6).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Seizure protein 6 homolog (SEZ6).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Seizure protein 6 homolog (SEZ6).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Seizure protein 6 homolog (SEZ6).	[13]

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 increases the methylation of Seizure protein 6 homolog (SEZ6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Seizure protein 6 homolog (SEZ6).	[12]

References

• [1] Exome sequencing in an Italian family with Alzheimer's disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H.Alzheimers Res Ther. 2018 Oct 12;10(1):106. doi: 10.1186/s13195-018-0435-2.
• [2] Febrile seizures are associated with mutation of seizure-related (SEZ) 6, a brain-specific gene.J Neurosci Res. 2007 Jan;85(1):166-72. doi: 10.1002/jnr.21103.
• [3] Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis.Int J Hematol. 2012 Oct;96(4):492-500. doi: 10.1007/s12185-012-1171-1. Epub 2012 Sep 13.
• [4] BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.PLoS One. 2018 Jul 6;13(7):e0200344. doi: 10.1371/journal.pone.0200344. eCollection 2018.
• [5] Lack of Sez6 Family Proteins Impairs Motor Functions, Short-Term Memory, and Cognitive Flexibility and Alters Dendritic Spine Properties.Cereb Cortex. 2020 Apr 14;30(4):2167-2184. doi: 10.1093/cercor/bhz230.
• [6] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [7] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] 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.
• [12] 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.
• [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.