Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3WLAD8)

• DOT Name: Probable arginine--tRNA ligase, mitochondrial (RARS2)
• Synonyms: EC 6.1.1.19; Arginyl-tRNA synthetase; ArgRS
• Gene Name: RARS2
• Related Disease:
  Mitochondrial disease
  Pontocerebellar hypoplasia type 6
  Epilepsy
  MELAS syndrome
  Mitochondrial encephalomyopathy
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia type 1A
  Sensory ataxia
  West syndrome
  Hydrops fetalis
  Isolated congenital microcephaly
  Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder
  PEHO syndrome
• UniProt ID: SYRM_HUMAN
• EC Number: 6.1.1.19
• Pfam ID: PF05746 ; PF00750
• Sequence:
  MACGFRRAIACQLSRVLNLPPENLITSISAVPISQKEEVADFQLSVDSLLEKDNDHSRPD
  IQVQAKRLAEKLRCDTVVSEISTGQRTVNFKINRELLTKTVLQQVIEDGSKYGLKSELFS
  GLPQKKIVVEFSSPNVAKKFHVGHLRSTIIGNFIANLKEALGHQVIRINYLGDWGMQFGL
  LGTGFQLFGYEEKLQSNPLQHLFEVYVQVNKEAADDKSVAKAAQEFFQRLELGDVQALSL
  WQKFRDLSIEEYIRVYKRLGVYFDEYSGESFYREKSQEVLKLLESKGLLLKTIKGTAVVD
  LSGNGDPSSICTVMRSDGTSLYATRDLAAAIDRMDKYNFDTMIYVTDKGQKKHFQQVFQM
  LKIMGYDWAERCQHVPFGVVQGMKTRRGDVTFLEDVLNEIQLRMLQNMASIKTTKELKNP
  QETAERVGLAALIIQDFKGLLLSDYKFSWDRVFQSRGDTGVFLQYTHARLHSLEETFGCG
  YLNDFNTACLQEPQSVSILQHLLRFDEVLYKSSQDFQPRHIVSYLLTLSHLAAVAHKTLQ
  IKDSPPEVAGARLHLFKAVRSVLANGMKLLGITPVCRM
• Function: Catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction: arginine is first activated by ATP to form Arg-AMP and then transferred to the acceptor end of tRNA(Arg).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Pontocerebellar hypoplasia type 6	DIS9BKLQ	Definitive	Autosomal recessive	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[4]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[5]
Pontocerebellar hypoplasia	DISRICMU	Strong	Biomarker	[6]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Strong	Genetic Variation	[7]
Sensory ataxia	DISSMCYQ	Strong	Genetic Variation	[4]
West syndrome	DISLIAU9	Strong	Genetic Variation	[6]
Hydrops fetalis	DISD9BBF	moderate	Genetic Variation	[8]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[9]
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	DISPBAUD	moderate	Genetic Variation	[10]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[11]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[10]
PEHO syndrome	DISPO5IP	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Probable arginine--tRNA ligase, mitochondrial (RARS2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable arginine--tRNA ligase, mitochondrial (RARS2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Probable arginine--tRNA ligase, mitochondrial (RARS2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Probable arginine--tRNA ligase, mitochondrial (RARS2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Probable arginine--tRNA ligase, mitochondrial (RARS2).	[17]

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] Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study. J Med Genet. 2022 Apr;59(4):399-409. doi: 10.1136/jmedgenet-2020-107497. Epub 2021 Mar 5.
• [3] Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.PLoS One. 2019 Mar 28;14(3):e0214250. doi: 10.1371/journal.pone.0214250. eCollection 2019.
• [4] Mitochondrial disease and epilepsy.Dev Med Child Neurol. 2012 May;54(5):397-406. doi: 10.1111/j.1469-8749.2011.04214.x. Epub 2012 Jan 28.
• [5] Cerebellar hypoplasia and brainstem thinning associated with severe white matter and basal ganglia abnormalities in a child with an mtDNA deletion.J Inherit Metab Dis. 2011 Dec;34(6):1225-7. doi: 10.1007/s10545-011-9376-7. Epub 2011 Aug 9.
• [6] RARS2 mutations in a sibship with infantile spasms.Epilepsia. 2016 May;57(5):e97-e102. doi: 10.1111/epi.13358. Epub 2016 Apr 8.
• [7] Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.Brain. 2011 Jan;134(Pt 1):143-56. doi: 10.1093/brain/awq287. Epub 2010 Oct 15.
• [8] Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.J Neuropathol Exp Neurol. 2015 Jul;74(7):688-703. doi: 10.1097/NEN.0000000000000209.
• [9] RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia.Eur J Paediatr Neurol. 2016 May;20(3):412-7. doi: 10.1016/j.ejpn.2016.02.012. Epub 2016 Mar 2.
• [10] Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations.J Biol Chem. 2018 Aug 31;293(35):13604-13615. doi: 10.1074/jbc.RA118.003400. Epub 2018 Jul 13.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome.Eur J Med Genet. 2020 Mar;63(3):103766. doi: 10.1016/j.ejmg.2019.103766. Epub 2019 Sep 16.
• [13] 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.
• [14] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.