Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9S47XC)

• DOT Name: Pejvakin (PJVK)
• Synonyms: Autosomal recessive deafness type 59 protein
• Gene Name: PJVK
• Related Disease:
  Auditory neuropathy
  Nonsyndromic genetic hearing loss
  Autosomal recessive nonsyndromic hearing loss 59
  Deafness
  Hearing loss, autosomal recessive
• UniProt ID: PJVK_HUMAN
• Pfam ID: PF04598
• Sequence:
  MFAAATKSFVKQVGDGGRLVPVPSLSEADKYQPLSLVVKKKRCFLFPRYKFTSTPFTLKD
  ILLGDREISAGISSYQLLNYEDESDVSLYGRRGNHIVNDVGINVAGSDSIAVKASFGIVT
  KHEVEVSTLLKEITTRKINFDHSLIRQSRSSRKAVLCVVMESIRTTRQCSLSVHAGIRGE
  AMRFHFMDEQNPKGRDKAIVFPAHTTIAFSVFELFIYLDGAFDLCVTSVSKGGFEREETA
  TFALLYRLRNILFERNRRVMDVISRSQLYLDDLFSDYYDKPLSMTDISLKEGTHIRVNLL
  NHNIPKGPCILCGMGNFKRETVYGCFQCSVDGQKYVRLHAVPCFDIWHKRMK
• Function: Peroxisome-associated protein required to protect auditory hair cells against noise-induced damage. Acts by regulating noise-induced peroxisome proliferation in auditory hair cells and neurons, and promoting autophagic degradation of damaged peroxisomes (pexophagy). Noise overexposure increases reactive oxygen species (ROS) levels, causing oxidative damage to auditory hair cells and resulting in hearing loss. PJVK acts as a ROS sensor that recruits the autophagy machinery to trigger pexophagy of peroxisomes damaged by oxidative stress. In addition to pexophagy, also required to promote peroxisome proliferation in response to sound overstimulation.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Auditory neuropathy	DISM6GAU	Definitive	Genetic Variation	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[2]
Autosomal recessive nonsyndromic hearing loss 59	DISJTIVN	Strong	Autosomal recessive	[3]
Deafness	DISKCLH4	Strong	Genetic Variation	[4]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pejvakin (PJVK).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pejvakin (PJVK).	[7]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Pejvakin (PJVK).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pejvakin (PJVK).	[9]

References

• [1] High frequency of autosomal-recessive DFNB59 hearing loss in an isolated Arab population in Israel.Clin Genet. 2012 Sep;82(3):271-6. doi: 10.1111/j.1399-0004.2011.01741.x. Epub 2011 Jul 18.
• [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] Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet. 2006 Jul;38(7):770-8. doi: 10.1038/ng1829. Epub 2006 Jun 25.
• [4] Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction.Hum Mutat. 2007 Jun;28(6):571-7. doi: 10.1002/humu.20478.
• [5] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [9] 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.