Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPLNL6U)

• DOT Name: Glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1)
• Gene Name: GRXCR1
• Related Disease:
  Nonsyndromic genetic hearing loss
  Autosomal recessive nonsyndromic hearing loss 25
  Deafness
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive
• UniProt ID: GRCR1_HUMAN
• Pfam ID: PF00462
• Sequence:
  MLKREMKPESDRPRKVRFRIASSHSGRVLKEVYEDGQPSGSLDSECASICGIDGLGDSDG
  QQNGHIESEGDENENDQDSLLVLARAASEKGFGTRRVNILSKNGTVRGVKYKVSAGQALF
  NNLTKVLQQPSTDLEFDRVVIYTTCLRVVRTTFERCELVRKIFQNHRVKFEEKNIALNGE
  YGKELDERCRRVSEAPSLPVVFIDGHYLGGAEKILSMNESGELQDILTKIERVQHPHECP
  SCGGFGFLPCSVCHGSKMSMFRNCFTDSFKALKCTACNENGLQRCKNCAG
• Function: May play a role in actin filament architecture in developing stereocilia of sensory cells.
• Tissue Specificity: Expressed at low levels in adult lung, brain and duodenum with moderate levels in testis. Highly expressed in fetal cochlea.
• 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
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Autosomal recessive nonsyndromic hearing loss 25	DISOKCVA	Strong	Autosomal recessive	[2]
Deafness	DISKCLH4	Strong	Biomarker	[2]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[3]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1).	[5]

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 Glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1).	[7]

References

• [1] 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.
• [2] Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. Am J Hum Genet. 2010 Feb 12;86(2):138-47. doi: 10.1016/j.ajhg.2009.12.017. Epub 2010 Feb 4.
• [3] Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins.Cell Rep. 2018 Oct 30;25(5):1281-1291.e4. doi: 10.1016/j.celrep.2018.10.005.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] 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.