Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQE1O25)

• DOT Name: Ganglioside-induced differentiation-associated protein 1 (GDAP1)
• Synonyms: GDAP1
• Gene Name: GDAP1
• Related Disease:
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2
  Charcot-Marie-Tooth disease axonal type 2C
  Charcot-Marie-Tooth disease axonal type 2K
  Charcot-Marie-Tooth disease recessive intermediate A
  Chronic obstructive pulmonary disease
  Demyelinating polyneuropathy
  Disorder of sexual differentiation
  Hereditary motor and sensory neuropathy
  Mitochondrial complex I deficiency
  Mitochondrial disease
  Neuroblastoma
  Peripheral neuropathy
  Polyneuropathy
  Rheumatoid arthritis
  Tooth disorder
  Alcohol dependence
  Congenital glaucoma
  Peripheral sensory neuropathies
  Autosomal dominant Charcot-Marie-Tooth disease type 2K
  Charcot-Marie-Tooth disease type 4A
  Charcot-Marie-Tooth disease type 4
  Charcot-Marie-Tooth disease type 3
• UniProt ID: GDAP1_HUMAN
• PDB ID: 7AIA; 7ALM; 7B2G; 7Q6J; 7Q6K; 7YWD; 8A4J; 8A4K
• Pfam ID: PF13410 ; PF13417
• Sequence:
  MAERQEEQRGSPPLRAEGKADAEVKLILYHWTHSFSSQKVRLVIAEKALKCEEHDVSLPL
  SEHNEPWFMRLNSTGEVPVLIHGENIICEATQIIDYLEQTFLDERTPRLMPDKESMYYPR
  VQHYRELLDSLPMDAYTHGCILHPELTVDSMIPAYATTRIRSQIGNTESELKKLAEENPD
  LQEAYIAKQKRLKSKLLDHDNVKYLKKILDELEKVLDQVETELQRRNEETPEEGQQPWLC
  GESFTLADVSLAVTLHRLKFLGFARRNWGNGKRPNLETYYERVLKRKTFNKVLGHVNNIL
  ISAVLPTAFRVAKKRAPKVLGTTLVVGLLAGVGYFAFMLFRKRLGSMILAFRPRPNYF
• Function: Regulates the mitochondrial network by promoting mitochondrial fission.
• Tissue Specificity: Highly expressed in whole brain and spinal cord. Predominant expression in central tissues of the nervous system not only in neurons but also in Schwann cells.
• Reactome Pathway: Class I peroxisomal membrane protein import (R-HSA-9603798)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Definitive	Semidominant	[1]
Charcot-Marie-Tooth disease type 2	DISR30O9	Definitive	Genetic Variation	[2]
Charcot-Marie-Tooth disease axonal type 2C	DIS1S5NJ	Strong	Genetic Variation	[3]
Charcot-Marie-Tooth disease axonal type 2K	DIS8250C	Strong	Autosomal dominant	[4]
Charcot-Marie-Tooth disease recessive intermediate A	DISMM1M7	Strong	Autosomal recessive	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[6]
Disorder of sexual differentiation	DISRMAEZ	Strong	Genetic Variation	[7]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Biomarker	[8]
Mitochondrial complex I deficiency	DIS13M7V	Strong	Genetic Variation	[9]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[11]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[12]
Polyneuropathy	DISB9G3W	Strong	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[14]
Tooth disorder	DISBXWAX	Strong	Genetic Variation	[15]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[16]
Congenital glaucoma	DISHN3GO	moderate	Biomarker	[17]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[18]
Autosomal dominant Charcot-Marie-Tooth disease type 2K	DIS8DMHE	Supportive	Autosomal dominant	[19]
Charcot-Marie-Tooth disease type 4A	DIS7XS5C	Supportive	Autosomal recessive	[20]
Charcot-Marie-Tooth disease type 4	DISM8IZN	Disputed	Genetic Variation	[21]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[8]

3 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 Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[29]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Ganglioside-induced differentiation-associated protein 1 (GDAP1).	[31]

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] A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family.J Peripher Nerv Syst. 2012 Sep;17(3):351-5. doi: 10.1111/j.1529-8027.2012.00414.x.
• [3] A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease.Neurogenetics. 2011 May;12(2):145-53. doi: 10.1007/s10048-011-0276-7. Epub 2011 Mar 2.
• [4] Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002 Jan;30(1):21-2. doi: 10.1038/ng796. Epub 2001 Dec 17.
• [5] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [6] Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot-Marie-Tooth disease reveals a varied and unusual phenotypic spectrum.J Peripher Nerv Syst. 2019 Mar;24(1):125-130. doi: 10.1111/jns.12305. Epub 2019 Feb 6.
• [7] Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype. Am J Med Genet A. 2008 Sep 15;146A(18):2412-6. doi: 10.1002/ajmg.a.32456.
• [8] Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.PLoS Genet. 2015 Apr 10;11(4):e1005115. doi: 10.1371/journal.pgen.1005115. eCollection 2015 Apr.
• [9] Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).Neurogenetics. 2009 Apr;10(2):145-50. doi: 10.1007/s10048-008-0166-9. Epub 2008 Dec 17.
• [10] A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K.Orphanet J Rare Dis. 2011 Dec 26;6:87. doi: 10.1186/1750-1172-6-87.
• [11] CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca(2+) entry-stimulated respiration.Sci Rep. 2017 Feb 21;7:42993. doi: 10.1038/srep42993.
• [12] Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease.J Cell Mol Med. 2008 Apr;12(2):679-89. doi: 10.1111/j.1582-4934.2007.00158.x. Epub 2007 Nov 16.
• [13] Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland.Neurogenetics. 2013 May;14(2):123-32. doi: 10.1007/s10048-013-0358-9. Epub 2013 Mar 3.
• [14] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [15] Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene.Neuromuscul Disord. 2004 Apr;14(4):261-4. doi: 10.1016/j.nmd.2004.01.003.
• [16] Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome.Epigenetics. 2016 Jun 2;11(6):456-63. doi: 10.1080/15592294.2016.1179411. Epub 2016 Apr 29.
• [17] Hereditary motor and sensory neuropathy with congenital glaucoma. Report on a family.Arq Neuropsiquiatr. 1999 Jun;57(2A):190-4. doi: 10.1590/s0004-282x1999000200004.
• [18] Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease.J Cell Biol. 2005 Sep 26;170(7):1067-78. doi: 10.1083/jcb.200507087. Epub 2005 Sep 19.
• [19] Charcot-Marie-Tooth Neuropathy Type 2 C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 1998 Sep 24 [updated 2016 Apr 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [20] GDAP1-Related Hereditary Motor and Sensory Neuropathy. 2004 May 11 [updated 2017 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [21] Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease.Neuromuscul Disord. 2003 Nov;13(9):720-8. doi: 10.1016/s0960-8966(03)00093-2.
• [22] 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.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [25] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [26] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [27] 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.
• [28] 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.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] 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.
• [31] 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.