Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFEV9SV)

• DOT Name: Mitochondrial outer membrane protein SLC25A46 (SLC25A46)
• Synonyms: Solute carrier family 25 member 46
• Gene Name: SLC25A46
• Related Disease:
  Neuropathy, hereditary motor and sensory, type 6B
  Peripheral neuropathy
  Cerebellar ataxia
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia, type 1E
  Spinal muscular atrophy
  Hereditary motor and sensory neuropathy type 6
  Pontocerebellar hypoplasia type 1
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 1
  Charcot-Marie-Tooth disease type 1A
  Charcot-Marie-Tooth disease type 1B
  Charcot-Marie-Tooth disease type 2
  Leigh syndrome
  Mitochondrial disease
• UniProt ID: S2546_HUMAN
• Pfam ID: PF00153
• Sequence:
  MHPRRPDGFDGLGYRGGARDEQGFGGAFPARSFSTGSDLGHWVTTPPDIPGSRNLHWGEK
  SPPYGVPTTSTPYEGPTEEPFSSGGGGSVQGQSSEQLNRFAGFGIGLASLFTENVLAHPC
  IVLRRQCQVNYHAQHYHLTPFTVINIMYSFNKTQGPRALWKGMGSTFIVQGVTLGAEGII
  SEFTPLPREVLHKWSPKQIGEHLLLKSLTYVVAMPFYSASLIETVQSEIIRDNTGILECV
  KEGIGRVIGMGVPHSKRLLPLLSLIFPTVLHGVLHYIISSVIQKFVLLILKRKTYNSHLA
  ESTSPVQSMLDAYFPELIANFAASLCSDVILYPLETVLHRLHIQGTRTIIDNTDLGYEVL
  PINTQYEGMRDCINTIRQEEGVFGFYKGFGAVIIQYTLHAAVLQITKIIYSTLLQNNI
• Function: Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization. May regulate the assembly of the MICOS (mitochondrial contact site and cristae organizing system) complex which is essential to the biogenesis and dynamics of mitochondrial cristae, the inwards folds of the inner mitochondrial membrane. Through its interaction with the EMC (endoplasmic reticulum membrane protein complex), could regulate mitochondrial lipid homeostasis and thereby mitochondrial fission.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuropathy, hereditary motor and sensory, type 6B	DIS8LL6H	Definitive	Autosomal recessive	[1]
Peripheral neuropathy	DIS7KN5G	Definitive	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[4]
Pontocerebellar hypoplasia, type 1E	DISLQGMB	Strong	Autosomal recessive	[2]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[5]
Hereditary motor and sensory neuropathy type 6	DIS27OAR	Supportive	Autosomal dominant	[6]
Pontocerebellar hypoplasia type 1	DISU1PSQ	Supportive	Autosomal recessive	[7]
Charcot marie tooth disease	DIS3BT2L	Disputed	Biomarker	[6]
Charcot-Marie-Tooth disease type 1	DIS56F9A	Disputed	Biomarker	[6]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Disputed	Biomarker	[6]
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Disputed	Biomarker	[6]
Charcot-Marie-Tooth disease type 2	DISR30O9	Limited	Genetic Variation	[8]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[20]

3 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 Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mitochondrial outer membrane protein SLC25A46 (SLC25A46).	[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] Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia. Brain. 2016 Nov 1;139(11):2877-2890. doi: 10.1093/brain/aww212.
• [3] Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.Hum Mol Genet. 2017 Oct 1;26(19):3776-3791. doi: 10.1093/hmg/ddx262.
• [4] Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.Clin Genet. 2018 Feb;93(2):255-265. doi: 10.1111/cge.13084. Epub 2017 Nov 8.
• [5] Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature.Eur J Paediatr Neurol. 2018 Jul;22(4):674-681. doi: 10.1016/j.ejpn.2018.03.011. Epub 2018 Apr 3.
• [6] Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet. 2015 Aug;47(8):926-32. doi: 10.1038/ng.3354. Epub 2015 Jul 13.
• [7] Pontocerebellar hypoplasia with spinal muscular atrophy (PCH1): identification of SLC25A46 mutations in the original Dutch PCH1 family. Brain. 2017 Aug 1;140(8):e46. doi: 10.1093/brain/awx147.
• [8] Reduction of Rpd3 suppresses defects in locomotive ability and neuronal morphology induced by the knockdown of Drosophila SLC25A46 via an epigenetic pathway.Exp Cell Res. 2019 Dec 15;385(2):111673. doi: 10.1016/j.yexcr.2019.111673. Epub 2019 Oct 12.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.