Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFWZSV7)

• DOT Name: Nesprin-4 (SYNE4)
• Synonyms: KASH domain-containing protein 4; KASH4; Nuclear envelope spectrin repeat protein 4
• Gene Name: SYNE4
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 76
  Nonsyndromic genetic hearing loss
  Hearing loss, autosomal recessive
• UniProt ID: SYNE4_HUMAN
• PDB ID: 6R16; 6WMD
• Pfam ID: PF10541
• Sequence:
  MALSLPLGPRLGSEPLNHPPGAPREADIVGCTVCPASGEESTSPEQAQTLGQDSLGPPEH
  FQGGPRGNEPAAHPPRWSTPSSYEDPAGGKHCEHPISGLEVLEAEQNSLHLCLLGLGRRL
  QDLEQGLGHWALAQSGMVQLQALQVDLRGAAERVEALLAFGEGLAQRSEPRAWAALEQIL
  RALGAYRDSIFRRLWQLQAQLVSYSLVFEEANTLDQDLEVEGDSDWPGPGGVWGPWAPSS
  LPTSTELEWDPAGDIGGLGPLGQKTARTLGVPCELCGQRGPQGRGQGLEEADTSHSRQDM
  LESGLGHQKRLARHQRHSLLRKPQDKKRQASPHLQDVRLEGNPGAPDPASRQPLTFLLIL
  FLLFLLLVGAMFLLPASGGPCCSHARIPRTPYLVLSYVNGLPPV
• Function: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Behaves as a kinesin cargo, providing a functional binding site for kinesin-1 at the nuclear envelope. Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 76	DISBNROI	Strong	Autosomal recessive	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Moderate	Autosomal recessive	[2]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[1]

5 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 Nesprin-4 (SYNE4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nesprin-4 (SYNE4).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nesprin-4 (SYNE4).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nesprin-4 (SYNE4).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nesprin-4 (SYNE4).	[7]

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 Nesprin-4 (SYNE4).	[8]

References

• [1] The LINC complex is essential for hearing. J Clin Invest. 2013 Feb;123(2):740-50. doi: 10.1172/JCI66911. Epub 2013 Jan 25.
• [2] 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.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.