Details of Drug Off-Target (DOT)

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

• DOT Name: 43 kDa receptor-associated protein of the synapse (RAPSN)
• Synonyms: RAPsyn; 43 kDa postsynaptic protein; Acetylcholine receptor-associated 43 kDa protein; RING finger protein 205
• Gene Name: RAPSN
• Related Disease:
  Fetal akinesia deformation sequence 1
  Arthrogryposis
  Atopic dermatitis
  Autoimmune disease
  Autosomal recessive multiple pterygium syndrome
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Congenital myasthenic syndrome
  Congenital myasthenic syndrome 11
  Congenital myasthenic syndrome 4C
  Coronary atherosclerosis
  Coronary heart disease
  Depression
  Familial spontaneous pneumothorax
  Fetal akinesia deformation sequence 2
  Heroin dependence
  Inflammatory bowel disease
  Major depressive disorder
  Mood disorder
  Obesity
  Polycystic ovarian syndrome
  Progressive supranuclear palsy
  Asthma
  Cardiovascular disease
  Myopathy
  Type-1/2 diabetes
  Postsynaptic congenital myasthenic syndrome
  Prostate cancer
  Prostate carcinoma
  Gastric cancer
  Limb-girdle muscular dystrophy
  Stomach cancer
• UniProt ID: RAPSN_HUMAN
• Pfam ID: PF10579 ; PF17874 ; PF13639
• Sequence:
  MGQDQTKQQIEKGLQLYQSNQTEKALQVWTKVLEKSSDLMGRFRVLGCLVTAHSEMGRYK
  EMLKFAVVQIDTARELEDADFLLESYLNLARSNEKLCEFHKTISYCKTCLGLPGTRAGAQ
  LGGQVSLSMGNAFLGLSVFQKALESFEKALRYAHNNDDAMLECRVCCSLGSFYAQVKDYE
  KALFFPCKAAELVNNYGKGWSLKYRAMSQYHMAVAYRLLGRLGSAMECCEESMKIALQHG
  DRPLQALCLLCFADIHRSRGDLETAFPRYDSAMSIMTEIGNRLGQVQALLGVAKCWVARK
  ALDKALDAIERAQDLAEEVGNKLSQLKLHCLSESIYRSKGLQRELRAHVVRFHECVEETE
  LYCGLCGESIGEKNSRLQALPCSHIFHLRCLQNNGTRSCPNCRRSSMKPGFV
• Function: Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. It may link the receptor to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin.

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fetal akinesia deformation sequence 1	DISKDI9L	Definitive	Autosomal recessive	[1]
Arthrogryposis	DISC81CM	Strong	CausalMutation	[2]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Autosomal recessive multiple pterygium syndrome	DISVK1D4	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[7]
Congenital myasthenic syndrome 11	DISCPZS5	Strong	Autosomal recessive	[8]
Congenital myasthenic syndrome 4C	DISWUJS0	Strong	CausalMutation	[9]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[10]
Depression	DIS3XJ69	Strong	Genetic Variation	[11]
Familial spontaneous pneumothorax	DISNM7SU	Strong	Biomarker	[12]
Fetal akinesia deformation sequence 2	DISMNQ3E	Strong	Autosomal recessive	[1]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[13]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[14]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[11]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[15]
Obesity	DIS47Y1K	Strong	Genetic Variation	[16]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[17]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[12]
Asthma	DISW9QNS	moderate	Altered Expression	[18]
Cardiovascular disease	DIS2IQDX	moderate	Genetic Variation	[19]
Myopathy	DISOWG27	moderate	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[20]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[21]
Prostate cancer	DISF190Y	Disputed	Biomarker	[22]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[22]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[23]
Limb-girdle muscular dystrophy	DISI9Y1Z	Limited	Biomarker	[24]
Stomach cancer	DISKIJSX	Limited	Genetic Variation	[23]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 43 kDa receptor-associated protein of the synapse (RAPSN).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 43 kDa receptor-associated protein of the synapse (RAPSN).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 43 kDa receptor-associated protein of the synapse (RAPSN).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 43 kDa receptor-associated protein of the synapse (RAPSN).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 43 kDa receptor-associated protein of the synapse (RAPSN).	[28]

References

• [1] Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008 Jan;82(1):222-7. doi: 10.1016/j.ajhg.2007.09.016.
• [2] The genomic and clinical landscape of fetal akinesia.Genet Med. 2020 Mar;22(3):511-523. doi: 10.1038/s41436-019-0680-1. Epub 2019 Nov 4.
• [3] Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort).Nutrients. 2015 Dec 3;7(12):10100-15. doi: 10.3390/nu7125521.
• [4] Antirapsyn antibodies in chronic procainamide-associated myopathy (CPAM).Ann N Y Acad Sci. 1998 May 13;841:527-9. doi: 10.1111/j.1749-6632.1998.tb10975.x.
• [5] Altered polyunsaturated fatty acid levels in relation to proinflammatory cytokines, fatty acid desaturase genotype, and diet in bipolar disorder.Transl Psychiatry. 2019 Aug 27;9(1):208. doi: 10.1038/s41398-019-0536-0.
• [6] DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA.Oncotarget. 2016 Sep 27;7(39):64191-64202. doi: 10.18632/oncotarget.11640.
• [7] Null variants in AGRN cause lethal fetal akinesia deformation sequence.Clin Genet. 2020 Apr;97(4):634-638. doi: 10.1111/cge.13677. Epub 2019 Dec 11.
• [8] 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.
• [9] Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients.Muscle Nerve. 2011 Apr;43(4):574-7. doi: 10.1002/mus.21919. Epub 2011 Feb 8.
• [10] -5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators.Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):218-231. doi: 10.1161/ATVBAHA.117.309660. Epub 2017 Oct 26.
• [11] Erythrocyte polyunsaturated fatty acid composition is associated with depression and FADS genotype in Caucasians.Nutr Neurosci. 2018 Oct;21(8):589-601. doi: 10.1080/1028415X.2017.1327685. Epub 2017 May 29.
• [12] Pena-Shokeir phenotype (fetal akinesia deformation sequence) revisited.Birth Defects Res A Clin Mol Teratol. 2009 Aug;85(8):677-94. doi: 10.1002/bdra.20611.
• [13] Genetic polymorphisms of FADS1, FADS2, and FADS3 and fatty acid profiles in subjects received methadone maintenance therapy. Prostaglandins Leukot Essent Fatty Acids. 2018 Sep;136:117-121.
• [14] Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis.Prostaglandins Leukot Essent Fatty Acids. 2018 Mar;130:1-10. doi: 10.1016/j.plefa.2018.02.002. Epub 2018 Feb 19.
• [15] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [16] The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden: the GLACIER Study.Int J Obes (Lond). 2019 Apr;43(4):808-820. doi: 10.1038/s41366-018-0112-3. Epub 2018 May 24.
• [17] FADS1-FADS2 gene cluster confers risk to polycystic ovary syndrome.Sci Rep. 2016 Feb 16;6:21195. doi: 10.1038/srep21195.
• [18] Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.Br J Nutr. 2015 Sep 28;114(6):891-8. doi: 10.1017/S0007114515002561. Epub 2015 Aug 18.
• [19] One-Carbon Metabolism and Lipid Metabolism in DOHaD.Adv Exp Med Biol. 2018;1012:3-9. doi: 10.1007/978-981-10-5526-3_1.
• [20] Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome.Br J Nutr. 2012 Feb;107(4):547-55. doi: 10.1017/S0007114511003230. Epub 2011 Jul 4.
• [21] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 23]. 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.
• [22] Impact of Genetic and Epigenetic Variations Within the FADS Cluster on the Composition and Metabolism of Polyunsaturated Fatty Acids in Prostate Cancer.Prostate. 2016 Sep;76(13):1182-91. doi: 10.1002/pros.23205. Epub 2016 May 16.
• [23] Dietary n-3 and n-6 polyunsaturated fatty acids, the FADS gene, and the risk of gastric cancer in a Korean population.Sci Rep. 2018 Feb 28;8(1):3823. doi: 10.1038/s41598-018-21960-3.
• [24] Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.Lancet Neurol. 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7.
• [25] 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.
• [26] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [27] 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.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.