Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT579DMU)

• DOT Name: Protein Mpv17 (MPV17)
• Gene Name: MPV17
• Related Disease:
  Glomerulosclerosis
  Mitochondrial disease
  Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
  Arteriosclerosis
  Charcot-Marie-Tooth disease, axonal, type 2EE
  Cholestasis
  Coenzyme Q10 deficiency
  Focal segmental glomerulosclerosis
  Gout
  High blood pressure
  IgA nephropathy
  Kidney failure
  Leukodystrophy
  Liver cirrhosis
  Liver failure
  Mitochondrial DNA depletion syndrome 4a
  Mitochondrial DNA depletion syndrome, hepatocerebral form
  Mitochondrial myopathy
  Multiple synostoses syndrome
  Myelodysplastic syndrome
  Myopathy
  Nephropathy
  Nephrotic syndrome
  Peripheral neuropathy
  Polyneuropathy
  Proximal symphalangism
  Mitochondrial DNA depletion syndrome
  Autosomal recessive Alport syndrome
• UniProt ID: MPV17_HUMAN
• Pfam ID: PF04117
• Sequence:
  MALWRAYQRALAAHPWKVQVLTAGSLMGLGDIISQQLVERRGLQEHQRGRTLTMVSLGCG
  FVGPVVGGWYKVLDRFIPGTTKVDALKKMLLDQGGFAPCFLGCFLPLVGALNGLSAQDNW
  AKLQRDYPDALITNYYLWPAVQLANFYLVPLHYRLAVVQCVAVIWNSYLSWKAHRL
• Function: Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis. Involved in mitochondrial deoxynucleoside triphosphates (dNTP) pool homeostasis and mitochondrial DNA (mtDNA) maintenance. May be involved in the regulation of reactive oxygen species metabolism and the control of oxidative phosphorylation.
• Tissue Specificity: Ubiquitous. Expressed in pancreas, kidney, muscle, liver, lung, placenta, brain and heart.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway: Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glomerulosclerosis	DISJF20Z	Definitive	Biomarker	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	DISBXRM2	Definitive	Autosomal recessive	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Charcot-Marie-Tooth disease, axonal, type 2EE	DISLBBZC	Strong	Autosomal recessive	[5]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[6]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[7]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[8]
Gout	DISHC0U7	Strong	Genetic Variation	[9]
High blood pressure	DISY2OHH	Strong	Biomarker	[10]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[11]
Kidney failure	DISOVQ9P	Strong	Biomarker	[1]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[12]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[8]
Liver failure	DISLGEL6	Strong	Genetic Variation	[13]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Strong	Genetic Variation	[14]
Mitochondrial DNA depletion syndrome, hepatocerebral form	DISXOJLH	Strong	Genetic Variation	[15]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[7]
Multiple synostoses syndrome	DISGA3UA	Strong	Genetic Variation	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[17]
Myopathy	DISOWG27	Strong	Biomarker	[18]
Nephropathy	DISXWP4P	Strong	Biomarker	[8]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[19]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[18]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[12]
Proximal symphalangism	DISK9LH5	Strong	Genetic Variation	[20]
Mitochondrial DNA depletion syndrome	DISIGZSM	moderate	Genetic Variation	[21]
Autosomal recessive Alport syndrome	DISFOQZB	Limited	Biomarker	[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 Protein Mpv17 (MPV17).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein Mpv17 (MPV17).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein Mpv17 (MPV17).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Mpv17 (MPV17).	[25]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein Mpv17 (MPV17).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Mpv17 (MPV17).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Mpv17 (MPV17).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Mpv17 (MPV17).	[29]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Protein Mpv17 (MPV17).	[30]

References

• [1] SYM1 is the stress-induced Saccharomyces cerevisiae ortholog of the mammalian kidney disease gene Mpv17 and is required for ethanol metabolism and tolerance during heat shock.Eukaryot Cell. 2004 Jun;3(3):620-31. doi: 10.1128/EC.3.3.620-631.2004.
• [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] MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet. 2006 May;38(5):570-5. doi: 10.1038/ng1765. Epub 2006 Apr 2.
• [4] Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney.J Am Soc Nephrol. 2019 Aug;30(8):1471-1480. doi: 10.1681/ASN.2019020183. Epub 2019 Jul 5.
• [5] A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. BMC Neurol. 2015 Oct 5;15:179. doi: 10.1186/s12883-015-0430-1.
• [6] Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.J Pediatr. 2014 Mar;164(3):553-9.e1-2. doi: 10.1016/j.jpeds.2013.10.082. Epub 2013 Dec 8.
• [7] Mitochondrial myopathies.Curr Opin Rheumatol. 2006 Nov;18(6):636-41. doi: 10.1097/01.bor.0000245729.17759.f2.
• [8] Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.Hum Mol Genet. 2009 Jan 1;18(1):12-26. doi: 10.1093/hmg/ddn309. Epub 2008 Sep 24.
• [9] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [10] Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice.Mol Biol Cell. 1998 Jul;9(7):1675-82. doi: 10.1091/mbc.9.7.1675.
• [11] Crescents and Global Glomerulosclerosis in Chinese IgA Nephropathy Patients: A Five-Year Follow-Up.Kidney Blood Press Res. 2019;44(1):103-112. doi: 10.1159/000498874. Epub 2019 Feb 22.
• [12] Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form.Mol Genet Metab. 2008 Jun;94(2):234-9. doi: 10.1016/j.ymgme.2008.01.012. Epub 2008 Mar 10.
• [13] Clinical and molecular characterization of three patients with Hepatocerebral form of mitochondrial DNA depletion syndrome: a case series.BMC Med Genet. 2019 Oct 29;20(1):167. doi: 10.1186/s12881-019-0893-9.
• [14] Mitochondrial syndromes with leukoencephalopathies.Semin Neurol. 2012 Feb;32(1):55-61. doi: 10.1055/s-0032-1306387. Epub 2012 Mar 15.
• [15] Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of Barth syndrome.Dis Model Mech. 2017 Apr 1;10(4):439-450. doi: 10.1242/dmm.027540. Epub 2017 Feb 10.
• [16] Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet. 1999 Mar;21(3):302-4. doi: 10.1038/6821.
• [17] Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene.Saudi J Gastroenterol. 2012 Jul-Aug;18(4):285-9. doi: 10.4103/1319-3767.98439.
• [18] MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.Hum Mutat. 2018 Apr;39(4):461-470. doi: 10.1002/humu.23387. Epub 2018 Jan 13.
• [19] Loss of auditory function in transgenic Mpv17-deficient mice.Hear Res. 1997 Dec;114(1-2):259-63. doi: 10.1016/s0378-5955(97)00175-5.
• [20] Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family.BMC Med Genet. 2019 Aug 1;20(1):133. doi: 10.1186/s12881-019-0864-1.
• [21] A defect in the mitochondrial protein Mpv17 underlies the transparent casper zebrafish.Dev Biol. 2017 Oct 1;430(1):11-17. doi: 10.1016/j.ydbio.2017.07.017. Epub 2017 Jul 28.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [24] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [25] 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.
• [26] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] 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.
• [29] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [30] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.