Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ0QH1P)

• DOT Name: Tetratricopeptide repeat protein 19, mitochondrial (TTC19)
• Synonyms: TPR repeat protein 19
• Gene Name: TTC19
• Related Disease:
  Leigh syndrome
  Mitochondrial complex III deficiency nuclear type 1
  Cerebellar ataxia
  Infertility
  Mitochondrial complex III deficiency nuclear type 2
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Nervous system disease
  Mitochondrial complex III deficiency
  Stroke
• UniProt ID: TTC19_HUMAN
• Pfam ID: PF13374 ; PF13424
• Sequence:
  MFRLLSWSLGRGFLRAAGRRCRGCSARLLPGLAGGPGPEVQVPPSRVAPHGRGPGLLPLL
  AALAWFSRPAAAEEEEQQGADGAAAEDGADEAEAEIIQLLKRAKLSIMKDEPEEAELILH
  DALRLAYQTDNKKAITYTYDLMANLAFIRGQLENAEQLFKATMSYLLGGGMKQEDNAIIE
  ISLKLASIYAAQNRQEFAVAGYEFCISTLEEKIEREKELAEDIMSVEEKANTHLLLGMCL
  DACARYLLFSKQPSQAQRMYEKALQISEEIQGERHPQTIVLMSDLATTLDAQGRFDEAYI
  YMQRASDLARQINHPELHMVLSNLAAVLMHRERYTQAKEIYQEALKQAKLKKDEISVQHI
  REELAELSKKSRPLTNSVKL
• Function: Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1. Involved in the clearance of UQCRFS1 N-terminal fragments, which are produced upon incorporation of UQCRFS1 into the complex III and whose presence is detrimental for its catalytic activity.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Mitochondrial complex III deficiency nuclear type 1	DISTXS4G	Definitive	Autosomal recessive	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Infertility	DISAMOWP	Strong	Biomarker	[4]
Mitochondrial complex III deficiency nuclear type 2	DIS6YL1O	Strong	Autosomal recessive	[5]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[6]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[7]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[3]
Mitochondrial complex III deficiency	DISSUPJ6	Supportive	Autosomal recessive	[4]
Stroke	DISX6UHX	Limited	Genetic Variation	[8]

2 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 Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Tetratricopeptide repeat protein 19, mitochondrial (TTC19).	[13]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation.J Hum Genet. 2015 Apr;60(4):187-91. doi: 10.1038/jhg.2015.7. Epub 2015 Feb 5.
• [4] Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet. 2011 Mar;43(3):259-63. doi: 10.1038/ng.761. Epub 2011 Jan 30.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Mitochondrial complex III Rieske Fe-S protein processing and assembly.Cell Cycle. 2018;17(6):681-687. doi: 10.1080/15384101.2017.1417707. Epub 2018 Apr 10.
• [7] Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency.Neurogenetics. 2013 May;14(2):153-60. doi: 10.1007/s10048-013-0361-1. Epub 2013 Mar 28.
• [8] Novel Homozygous Variant in TTC19 Causing Mitochondrial Complex III Deficiency with Recurrent Stroke-Like Episodes: Expanding the Phenotype.Semin Pediatr Neurol. 2018 Jul;26:16-20. doi: 10.1016/j.spen.2018.04.003.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.