Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHTJO2I)

• DOT Name: Junctophilin-3 (JPH3)
• Synonyms: JP-3; Junctophilin type 3; Trinucleotide repeat-containing gene 22 protein
• Gene Name: JPH3
• Related Disease:
  Cerebrovascular disease
  Huntington disease-like 2
  Hypercholesterolemia, familial, 1
  Hypobetalipoproteinemia
  Abetalipoproteinemia
  Cardiovascular disease
  Cholesterol-ester transfer protein deficiency
  Chorea-acanthocytosis
  Coronary atherosclerosis
  Coronary heart disease
  Dentatorubral-pallidoluysian atrophy
  Friedreich's ataxia
  High blood pressure
  Hyperlipidemia, familial combined, LPL related
  Movement disorder
  Myocardial infarction
  Myotonic dystrophy
  Neoplasm
  Neuroferritinopathy
  Obesity
  Spinocerebellar ataxia type 2
  Type-1/2 diabetes
  Spinocerebellar ataxia type 17
  Stroke
  Colorectal carcinoma
  Colorectal neoplasm
  Amyotrophic lateral sclerosis
  Arteriosclerosis
  Atherosclerosis
  Dementia
  Hyperlipidemia
  Neuromuscular disease
  Non-insulin dependent diabetes
  Primary biliary cholangitis
  Vitamin deficiency
• UniProt ID: JPH3_HUMAN
• Pfam ID: PF02493
• Sequence:
  MSSGGRFNFDDGGSYCGGWEDGKAHGHGVCTGPKGQGEYTGSWSHGFEVLGVYTWPSGNT
  YQGTWAQGKRHGIGLESKGKWVYKGEWTHGFKGRYGVRECAGNGAKYEGTWSNGLQDGYG
  TETYSDGGTYQGQWVGGMRQGYGVRQSVPYGMAAVIRSPLRTSINSLRSEHTNGTALHPD
  ASPAVAGSPAVSRGGFVLVAHSDSEILKSKKKGLFRRSLLSGLKLRKSESKSSLASQRSK
  QSSFRSEAGMSTVSSTASDIHSTISLGEAEAELAVIEDDIDATTTETYVGEWKNDKRSGF
  GVSQRSDGLKYEGEWASNRRHGYGCMTFPDGTKEEGKYKQNILVGGKRKNLIPLRASKIR
  EKVDRAVEAAERAATIAKQKAEIAASRTSHSRAKAEAALTAAQKAQEEARIARITAKEFS
  PSFQHRENGLEYQRPKRQTSCDDIEVLSTGTPLQQESPELYRKGTTPSDLTPDDSPLQSF
  PTSPAATPPPAPAARNKVAHFSRQVSVDEERGGDIQMLLEGRAGDCARSSWGEEQAGGSR
  GVRSGALRGGLLVDDFRTRGSGRKQPGNPKPRERRTESPPVFTWTSHHRASNHSPGGSRL
  LELQEEKLSNYRMEMKPLLRMETHPQKRRYSKGGACRGLGDDHRPEDRGFGVQRLRSKAQ
  NKENFRPASSAEPAVQKLASLRLGGAEPRLLRWDLTFSPPQKSLPVALESDEENGDELKS
  STGSAPILVVMVILLNIGVAILFINFFI
• Function: Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH3 is brain-specific and appears to have an active role in certain neurons involved in motor coordination and memory.
• Tissue Specificity: Specifically expressed in brain.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebrovascular disease	DISAB237	Definitive	Biomarker	[1]
Huntington disease-like 2	DISM3G09	Definitive	Autosomal dominant	[2]
Hypercholesterolemia, familial, 1	DISU411W	Definitive	Biomarker	[3]
Hypobetalipoproteinemia	DIS0TPI3	Definitive	Biomarker	[4]
Abetalipoproteinemia	DISMSS7T	Strong	Biomarker	[5]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[6]
Cholesterol-ester transfer protein deficiency	DISP9UAV	Strong	Biomarker	[7]
Chorea-acanthocytosis	DISW1V6N	Strong	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[8]
Dentatorubral-pallidoluysian atrophy	DISHWE0K	Strong	Biomarker	[9]
Friedreich's ataxia	DIS5DV35	Strong	Genetic Variation	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[11]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[12]
Movement disorder	DISOJJ2D	Strong	Biomarker	[13]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[14]
Myotonic dystrophy	DISNBEMX	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Neuroferritinopathy	DIS0E4F3	Strong	Altered Expression	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Spinocerebellar ataxia type 2	DISF7WDI	Strong	Genetic Variation	[19]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[20]
Spinocerebellar ataxia type 17	DISJXO7P	moderate	Genetic Variation	[21]
Stroke	DISX6UHX	moderate	Genetic Variation	[22]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[23]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[23]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[24]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[25]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[25]
Dementia	DISXL1WY	Limited	Genetic Variation	[26]
Hyperlipidemia	DIS61J3S	Limited	Genetic Variation	[27]
Neuromuscular disease	DISQTIJZ	Limited	Biomarker	[24]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[20]
Primary biliary cholangitis	DIS43E0O	Limited	Biomarker	[25]
Vitamin deficiency	DISD07I9	Limited	Biomarker	[28]

6 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 Junctophilin-3 (JPH3).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Junctophilin-3 (JPH3).	[30]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Junctophilin-3 (JPH3).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Junctophilin-3 (JPH3).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Junctophilin-3 (JPH3).	[37]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Junctophilin-3 (JPH3).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Junctophilin-3 (JPH3).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Junctophilin-3 (JPH3).	[32]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Junctophilin-3 (JPH3).	[33]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Junctophilin-3 (JPH3).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Junctophilin-3 (JPH3).	[38]

References

• [1] Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.Curr Opin Lipidol. 2003 Apr;14(2):179-89. doi: 10.1097/00041433-200304000-00010.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia.Arterioscler Thromb Vasc Biol. 2011 Jul;31(7):1675-81. doi: 10.1161/ATVBAHA.111.227181. Epub 2011 Apr 28.
• [4] Current state of knowledge in Chorea-Acanthocytosis as core Neuroacanthocytosis syndrome.Eur J Med Genet. 2018 Nov;61(11):699-705. doi: 10.1016/j.ejmg.2017.12.007. Epub 2017 Dec 16.
• [5] Familial hypobetalipoproteinemia--differences in lipoprotein structure and composition.Ann Nutr Metab. 1993;37(5):253-61. doi: 10.1159/000177775.
• [6] Impact of high-density lipoprotein 3 cholesterol subfraction on periprocedural myocardial injury in patients who underwent elective percutaneous coronary intervention.Lipids Health Dis. 2018 Feb 2;17(1):21. doi: 10.1186/s12944-018-0670-3.
• [7] Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia.Atherosclerosis. 1976 Oct;25(1):131-6. doi: 10.1016/0021-9150(76)90055-1.
• [8] Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.PLoS One. 2017 Feb 16;12(2):e0171993. doi: 10.1371/journal.pone.0171993. eCollection 2017.
• [9] Huntington disease-like 2 (HDL2) in Venezuela: frequency and ethnic origin.J Hum Genet. 2013 Jan;58(1):3-6. doi: 10.1038/jhg.2012.111. Epub 2012 Sep 13.
• [10] Huntington's disease phenocopies are clinically and genetically heterogeneous.Mov Disord. 2008 Apr 15;23(5):716-20. doi: 10.1002/mds.21915.
• [11] Higher High Density Lipoprotein 2 (HDL2) to Total HDL Cholesterol Ratio Is Associated with a Lower Risk for Incident Hypertension.Diabetes Metab J. 2019 Feb;43(1):114-122. doi: 10.4093/dmj.2018.0053. Epub 2018 Sep 28.
• [12] An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia.Metabolism. 2004 Feb;53(2):153-8. doi: 10.1016/j.metabol.2003.09.007.
• [13] A South African mixed ancestry family with Huntington disease-like 2: clinical and genetic features.Mov Disord. 2007 Oct 31;22(14):2083-9. doi: 10.1002/mds.21672.
• [14] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [15] Huntington's disease--like 2 is associated with CUG repeat-containing RNA foci.Ann Neurol. 2007 Mar;61(3):272-82. doi: 10.1002/ana.21081.
• [16] Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers.Theranostics. 2017 May 30;7(7):2150-2163. doi: 10.7150/thno.18185. eCollection 2017.
• [17] Huntington's disease and Huntington's disease-like syndromes: an overview.Curr Opin Neurol. 2013 Aug;26(4):420-7. doi: 10.1097/WCO.0b013e3283632d90.
• [18] Lack of sex differences in high density lipoproteins in Pima Indians. Studies of obesity, lipase activities, and steroid hormones.Arteriosclerosis. 1987 May-Jun;7(3):292-300. doi: 10.1161/01.atv.7.3.292.
• [19] Huntington disease and Huntington disease-like in a case series from Brazil.Clin Genet. 2014 Oct;86(4):373-7. doi: 10.1111/cge.12283. Epub 2013 Oct 17.
• [20] Different inverse association of large high-density lipoprotein subclasses with exacerbation of insulin resistance and incidence of type 2 diabetes: The Nagahama study.Diabetes Res Clin Pract. 2017 May;127:123-131. doi: 10.1016/j.diabres.2017.03.018. Epub 2017 Mar 21.
• [21] Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene.Neurol Neurochir Pol. 2008 May-Jun;42(3):203-9.
• [22] Identification of high risk relatives for coronary heart disease.J Am Coll Cardiol. 1988 Oct;12(4):1110-3. doi: 10.1016/0735-1097(88)90487-1.
• [23] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [24] Evaluating noncoding nucleotide repeat expansions in amyotrophic lateral sclerosis.Neurobiol Aging. 2014 Apr;35(4):936.e1-4. doi: 10.1016/j.neurobiolaging.2013.09.024. Epub 2013 Oct 23.
• [25] Lipoprotein(a) concentration and phenotypes in primary biliary cirrhosis.Clin Chim Acta. 1996 Nov 29;255(2):165-71. doi: 10.1016/0009-8981(96)06404-2.
• [26] JPH3 repeat expansions cause a progressive akinetic-rigid syndrome with severe dementia and putaminal rim in a five-generation African-American family.Neurogenetics. 2012 May;13(2):133-40. doi: 10.1007/s10048-012-0318-9. Epub 2012 Mar 25.
• [27] The management of the family at high risk for coronary heart disease.Cardiol Clin. 1989 May;7(2):467-77.
• [28] Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach.JAMA Neurol. 2016 Sep 1;73(9):1105-14. doi: 10.1001/jamaneurol.2016.2215.
• [29] 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.
• [30] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [31] 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.
• [32] 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.
• [33] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [34] 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.
• [35] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [36] 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.
• [37] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [38] 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.
• [39] 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.