Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA8TQU9)

• DOT Name: Gliomedin (GLDN)
• Gene Name: GLDN
• Related Disease:
  Advanced cancer
  Arthrogryposis
  Chronic inflammatory demyelinating polyneuropathy
  Hepatocellular carcinoma
  Lethal congenital contracture syndrome 11
  Multiple sclerosis
  Neoplasm
• UniProt ID: GLDN_HUMAN
• PDB ID: 5YBY
• Pfam ID: PF01391 ; PF02191
• Sequence:
  MARGAEGGRGDAGWGLRGALAAVALLSALNAAGTVFALCQWRGLSSALRALEAQRGREQR
  EDSALRSFLAELSRAPRGASAPPQDPASSARNKRSHSGEPAPHIRAESHDMLMMMTYSMV
  PIRVMVDLCNSTKGICLTGPSGPPGPPGAGGLPGHNGLDGQPGPQGPKGEKGANGKRGKM
  GIPGAAGNPGERGEKGDHGELGLQGNEGPPGQKGEKGDKGDVSNDVLLAGAKGDQGPPGP
  PGPPGPPGPPGPPGSRRAKGPRQPSMFNGQCPGETCAIPNDDTLVGKADEKASEHHSPQA
  ESMITSIGNPVQVLKVTETFGTWIRESANKSDDRIWVTEHFSGIMVKEFKDQPSLLNGSY
  TFIHLPYYFHGCGHVVYNNSLYYHKGGSNTLVRFEFGQETSQTLKLENALYFDRKYLFAN
  SKTYFNLAVDEKGLWIIYASSVDGSSILVAQLDERTFSVVQHVNTTYPKSKAGNAFIARG
  ILYVTDTKDMRVTFAFDLLGGKQINANFDLRTSQSVLAMLAYNMRDQHLYSWEDGHLMLY
  PVQFLSTTLNQ
• Function: Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Mediates interaction between Schwann cell microvilli and axons via its interactions with NRCAM and NFASC. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with NRCAM, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier.
• Tissue Specificity: Specifically expressed in spinal cord, brain, placenta and sciatic nerve. More abundant in peripheral than central nervous system.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arthrogryposis	DISC81CM	Strong	Genetic Variation	[2]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Lethal congenital contracture syndrome 11	DISEEF7H	Strong	Autosomal recessive	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Gliomedin (GLDN).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gliomedin (GLDN).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gliomedin (GLDN).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gliomedin (GLDN).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gliomedin (GLDN).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Gliomedin (GLDN).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gliomedin (GLDN).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Gliomedin (GLDN).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gliomedin (GLDN).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Gliomedin (GLDN).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gliomedin (GLDN).	[14]

References

• [1] Identification and characterization of CRG-L2, a new marker for liver tumor development.Oncogene. 2003 Mar 20;22(11):1730-6. doi: 10.1038/sj.onc.1206309.
• [2] The genomic and clinical landscape of fetal akinesia.Genet Med. 2020 Mar;22(3):511-523. doi: 10.1038/s41436-019-0680-1. Epub 2019 Nov 4.
• [3] Autoantibodies to neurofascin-186 and gliomedin in multifocal motor neuropathy.J Neuroimmunol. 2014 Nov 15;276(1-2):207-12. doi: 10.1016/j.jneuroim.2014.09.001. Epub 2014 Sep 16.
• [4] Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis. Am J Hum Genet. 2016 Oct 6;99(4):928-933. doi: 10.1016/j.ajhg.2016.07.021. Epub 2016 Sep 8.
• [5] Anti-neurofascin autoantibody and demyelination.Neurochem Int. 2019 Nov;130:104360. doi: 10.1016/j.neuint.2018.12.011. Epub 2018 Dec 22.
• [6] Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity.Int J Oncol. 2014 Oct;45(4):1583-93. doi: 10.3892/ijo.2014.2538. Epub 2014 Jul 8.
• [7] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [14] 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.
• [15] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.