Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCDHAM6)

• DOT Name: Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10)
• Synonyms: Protein N27C7-4
• Gene Name: CHCHD10
• Related Disease:
  Charcot-Marie-Tooth disease type 2
  Mitochondrial disease
  Alzheimer disease
  Amyotrophic lateral sclerosis type 1
  Autosomal dominant mitochondrial myopathy with exercise intolerance
  Cerebellar ataxia
  Deafness
  Dementia
  Familial amyotrophic lateral sclerosis
  Frontotemporal dementia
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 2
  Kennedy disease
  Lower motor neuron syndrome with late-adult onset
  Motor neurone disease
  Myopathy
  Nervous system disease
  Neuromuscular disease
  Parkinson disease
  Pick disease
  Amyotrophic lateral sclerosis
  Frontotemporal dementia with motor neuron disease
  Cardiomyopathy
  Spinal muscular atrophy
• UniProt ID: CHC10_HUMAN
• Pfam ID: PF06747
• Sequence:
  MPRGSRSAASRPASRPAAPSAHPPAHPPPSAAAPAPAPSGQPGLMAQMATTAAGVAVGSA
  VGHVMGSALTGAFSGGSSEPSQPAVQQAPTPAAPQPLQMGPCAYEIRQFLDCSTTQSDLS
  LCEGFSEALKQCKYYHGLSSLP
• Function: May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.
• Tissue Specificity: Ubiquitously expressed. Higher expression is observed in heart and liver.
• KEGG Pathway: Amyotrophic lateral sclerosis (hsa05014)
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 2	DISR30O9	Definitive	Biomarker	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal dominant	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Genetic Variation	[4]
Autosomal dominant mitochondrial myopathy with exercise intolerance	DIS5YQT0	Strong	Autosomal dominant	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Deafness	DISKCLH4	Strong	Genetic Variation	[6]
Dementia	DISXL1WY	Strong	Genetic Variation	[7]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[8]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[3]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1	DIS8SB8X	Strong	Genetic Variation	[9]
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2	DIS9LTNM	Strong	Autosomal dominant	[10]
Kennedy disease	DISXZVM1	Strong	Biomarker	[11]
Lower motor neuron syndrome with late-adult onset	DISBA5QM	Strong	Autosomal dominant	[5]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[3]
Myopathy	DISOWG27	Strong	Genetic Variation	[12]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[3]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[13]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[14]
Pick disease	DISP6X50	Strong	Biomarker	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[16]
Frontotemporal dementia with motor neuron disease	DISPZM6A	Supportive	Autosomal dominant	[10]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[17]
Spinal muscular atrophy	DISTLKOB	Limited	Genetic Variation	[18]

14 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 Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[24]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10).	[31]

References

• [1] CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.EMBO Mol Med. 2016 Jan 1;8(1):58-72. doi: 10.15252/emmm.201505496.
• [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] Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications.Neuroscientist. 2020 Apr;26(2):170-184. doi: 10.1177/1073858419871214. Epub 2019 Sep 16.
• [4] Mutation Screening of the CHCHD10 Gene in Chinese Patients with Amyotrophic Lateral Sclerosis.Mol Neurobiol. 2017 Jul;54(5):3189-3194. doi: 10.1007/s12035-016-9888-0. Epub 2016 Apr 7.
• [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] Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients.Neurobiol Aging. 2014 Dec;35(12):2884.e1-2884.e4. doi: 10.1016/j.neurobiolaging.2014.07.022. Epub 2014 Jul 24.
• [7] Identification of CHCHD10 Mutation in Chinese Patients with Alzheimer Disease.Mol Neurobiol. 2017 Sep;54(7):5243-5247. doi: 10.1007/s12035-016-0056-3. Epub 2016 Aug 30.
• [8] Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients.Neurobiol Aging. 2016 Jun;42:218.e1-3. doi: 10.1016/j.neurobiolaging.2016.03.022. Epub 2016 Mar 24.
• [9] Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases.Neurobiol Dis. 2018 Nov;119:159-171. doi: 10.1016/j.nbd.2018.07.027. Epub 2018 Aug 6.
• [10] A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014 Aug;137(Pt 8):2329-45. doi: 10.1093/brain/awu138. Epub 2014 Jun 16.
• [11] Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.PLoS One. 2016 Mar 21;11(3):e0151376. doi: 10.1371/journal.pone.0151376. eCollection 2016.
• [12] In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions.Hum Mol Genet. 2018 Jan 1;27(1):160-177. doi: 10.1093/hmg/ddx397.
• [13] Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.Hum Mol Genet. 2020 Jul 21;29(11):1784-1796. doi: 10.1093/hmg/ddz154.
• [14] CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I.Neurobiol Aging. 2019 Mar;75:38-41. doi: 10.1016/j.neurobiolaging.2018.10.020. Epub 2018 Oct 23.
• [15] Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice.J Neurol Neurosurg Psychiatry. 2020 Feb;91(2):162-171. doi: 10.1136/jnnp-2019-321790. Epub 2019 Nov 5.
• [16] Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014 Dec;137(Pt 12):e309. doi: 10.1093/brain/awu227. Epub 2014 Aug 11.
• [17] ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response.Acta Neuropathol. 2019 Jul;138(1):103-121. doi: 10.1007/s00401-019-01989-y. Epub 2019 Mar 14.
• [18] Mitochondrial CHCHD-Containing Proteins: Physiologic Functions and Link with Neurodegenerative Diseases.Mol Neurobiol. 2017 Sep;54(7):5534-5546. doi: 10.1007/s12035-016-0099-5. Epub 2016 Sep 8.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [29] 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.
• [30] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.