Details of Drug Off-Target (DOT)

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

• DOT Name: NADH dehydrogenase (NDUFAF6)
• Synonyms: ubiquinone) complex I, assembly factor 6 (Putative phytoene synthase
• Gene Name: NDUFAF6
• Related Disease:
  Fanconi's anemia
  Leigh syndrome
  Alzheimer disease
  Cardiovascular disease
  Dystonia
  Mitochondrial complex I deficiency
  Movement disorder
  Non-insulin dependent diabetes
  Mitochondrial complex 1 deficiency, nuclear type 17
  Obsolete Leigh syndrome with leukodystrophy
  Primary Fanconi syndrome
  Fanconi renotubular syndrome 5
• UniProt ID: NDUF6_HUMAN
• Pfam ID: PF00494
• Sequence:
  MAASAHGSVWGPLRLGIPGLCCRRPPLGLYARMRRLPGPEVSGRSVAAASGPGAWGTDHY
  CLELLRKRDYEGYLCSLLLPAESRSSVFALRAFNVELAQVKDSVSEKTIGLMRMQFWKKT
  VEDIYCDNPPHQPVAIELWKAVKRHNLTKRWLMKIVDEREKNLDDKAYRNIKELENYAEN
  TQSSLLYLTLEILGIKDLHADHAASHIGKAQGIVTCLRATPYHGSRRKVFLPMDICMLHG
  VSQEDFLRRNQDKNVRDVIYDIASQAHLHLKHARSFHKTVPVKAFPAFLQTVSLEDFLKK
  IQRVDFDIFHPSLQQKNTLLPLYLYIQSWRKTY
• Function: Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) at early stages. May play a role in the biogenesis of complex I subunit MT-ND1.
• Tissue Specificity: Widely expressed. A lower expression is observed in lung and kidney compared to heart, muscle and liver . In the kidney, expression is high in the basal zone of the proximal tubular cells .
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Complex I biogenesis (R-HSA-6799198)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi's anemia	DISGW6Q8	Definitive	Genetic Variation	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Dystonia	DISJLFGW	Strong	Genetic Variation	[5]
Mitochondrial complex I deficiency	DIS13M7V	Strong	Genetic Variation	[6]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[4]
Mitochondrial complex 1 deficiency, nuclear type 17	DISWQP98	Moderate	Autosomal recessive	[8]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[9]
Primary Fanconi syndrome	DISR144Y	Supportive	Autosomal dominant	[1]
Fanconi renotubular syndrome 5	DISV6FO2	Limited	Autosomal recessive	[8]

7 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 NADH dehydrogenase (NDUFAF6).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADH dehydrogenase (NDUFAF6).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase (NDUFAF6).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH dehydrogenase (NDUFAF6).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADH dehydrogenase (NDUFAF6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH dehydrogenase (NDUFAF6).	[16]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of NADH dehydrogenase (NDUFAF6).	[17]

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 increases the methylation of NADH dehydrogenase (NDUFAF6).	[14]

References

• [1] Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. Hum Mol Genet. 2016 Sep 15;25(18):4062-4079. doi: 10.1093/hmg/ddw245. Epub 2016 Jul 27.
• [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] Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.Alzheimers Dement. 2019 Oct;15(10):1333-1347. doi: 10.1016/j.jalz.2019.06.4950. Epub 2019 Aug 28.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [5] Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.Mol Genet Metab. 2019 Mar;126(3):250-258. doi: 10.1016/j.ymgme.2019.01.001. Epub 2019 Jan 5.
• [6] Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.J Hum Genet. 2018 May;63(5):563-568. doi: 10.1038/s10038-018-0423-1. Epub 2018 Mar 12.
• [7] A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. doi: 10.1371/journal.pgen.1005679. eCollection 2016 Jan.
• [8] 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.
• [9] A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008 Jul 11;134(1):112-23. doi: 10.1016/j.cell.2008.06.016.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.