Details of Drug Off-Target (DOT)

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

• DOT Name: Junctophilin-1 (JPH1)
• Synonyms: JP-1; Junctophilin type 1
• Gene Name: JPH1
• Related Disease:
  Narcolepsy
  Breast cancer
  Breast carcinoma
  Charcot-Marie-Tooth disease type 4A
  Colorectal carcinoma
  Polyneuropathy
  Charcot marie tooth disease
• UniProt ID: JPH1_HUMAN
• PDB ID: 7RW4
• Pfam ID: PF02493
• Sequence:
  MTGGRFDFDDGGTYCGGWEEGKAHGHGICTGPKGQGEYSGSWSHGFEVVGGYTWPSGNTY
  QGYWAQGKRHGLGVETKGKWMYRGEWSHGFKGRYGVRQSLCTPARYEGTWSNGLQDGYGV
  ETYGDGGTYQGQWAGGMRHGYGVRQSVPYGMATVIRSPLRTSLASLRSEQSNGSVLHDAA
  AAADSPAGTRGGFVLNFHADAELAGKKKGGLFRRGSLLGSMKLRKSESKSSISSKRSSVR
  SDAAMSRISSSDANSTISFGDVDCDFCPVEDHVDATTTETYMGEWKNDKRNGFGVSERSN
  GMKYEGEWANNKRHGYGCTVFPDGSKEEGKYKNNILVRGIRKQLIPIRHTKTREKVDRAI
  EGAQRAAAMARTKVEIANSRTAHARAKADAADQAALAARQECDIARAVARELSPDFYQPG
  PDYVKQRFQEGVDAKENPEEKVPEKPPTPKESPHFYRKGTTPPRSPEASPKHSHSPASSP
  KPLKKQNPSSGARLNQDKRSVADEQVTAIVNKPLMSKAPTKEAGAVVPQSKYSGRHHIPN
  PSNGELHSQYHGYYVKLNAPQHPPVDVEDGDGSSQSSSALVHKPSANKWSPSKSVTKPVA
  KESKAEPKAKKSELAIPKNPASNDSCPALEKEANSGPNSIMIVLVMLLNIGLAILFVHFL
  T
• 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. JPH1 contributes to the construction of the skeletal muscle triad by linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes.
• Tissue Specificity: Abundantly expressed in skeletal muscle. Very low levels in heart.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Charcot-Marie-Tooth disease type 4A	DIS7XS5C	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[4]
Charcot marie tooth disease	DIS3BT2L	moderate	Genetic Variation	[5]

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 Junctophilin-1 (JPH1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Junctophilin-1 (JPH1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Junctophilin-1 (JPH1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Junctophilin-1 (JPH1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Junctophilin-1 (JPH1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Junctophilin-1 (JPH1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Junctophilin-1 (JPH1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Junctophilin-1 (JPH1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Junctophilin-1 (JPH1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Junctophilin-1 (JPH1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Junctophilin-1 (JPH1).	[16]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Prospective validation in epithelial tumors of a gene expression predictor of liver metastasis derived from uveal melanoma.Sci Rep. 2019 Nov 20;9(1):17178. doi: 10.1038/s41598-019-52841-y.
• [3] A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.Acta Biochim Pol. 2014;61(4):739-44. Epub 2014 Oct 22.
• [4] Inherited mitochondrial neuropathies.J Neurol Sci. 2011 May 15;304(1-2):9-16. doi: 10.1016/j.jns.2011.02.012. Epub 2011 Mar 13.
• [5] Genotype-phenotype correlation and frequency of distribution in a cohort of Chinese Charcot-Marie-Tooth patients associated with GDAP1 mutations.J Neurol. 2018 Mar;265(3):637-646. doi: 10.1007/s00415-018-8743-9. Epub 2018 Jan 25.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [14] 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.
• [15] 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.
• [16] 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.