Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BS5V9)

• DOT Name: Cystinosin (CTNS)
• Gene Name: CTNS
• Related Disease:
  Cystinosis
  Nephropathic cystinosis
  Juvenile nephropathic cystinosis
  Ocular cystinosis
  Nephropathic infantile cystinosis
• UniProt ID: CTNS_HUMAN
• PDB ID: 8DKE; 8DKI; 8DKM; 8DKW; 8DKX; 8DYP
• Pfam ID: PF04193
• Sequence:
  MIRNWLTIFILFPLKLVEKCESSVSLTVPPVVKLENGSSTNVSLTLRPPLNATLVITFEI
  TFRSKNITILELPDEVVVPPGVTNSSFQVTSQNVGQLTVYLHGNHSNQTGPRIRFLVIRS
  SAISIINQVIGWIYFVAWSISFYPQVIMNWRRKSVIGLSFDFVALNLTGFVAYSVFNIGL
  LWVPYIKEQFLLKYPNGVNPVNSNDVFFSLHAVVLTLIIIVQCCLYERGGQRVSWPAIGF
  LVLAWLFAFVTMIVAAVGVTTWLQFLFCFSYIKLAVTLVKYFPQAYMNFYYKSTEGWSIG
  NVLLDFTGGSFSLLQMFLQSYNNDQWTLIFGDPTKFGLGVFSIVFDVVFFIQHFCLYRKR
  PGYDQLN
• Function: Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes. Plays an important role in melanin synthesis by catalyzing cystine export from melanosomes, possibly by inhibiting pheomelanin synthesis. In addition to cystine export, also acts as a positive regulator of mTORC1 signaling in kidney proximal tubular cells, via interactions with components of the v-ATPase and Ragulator complexes. Also involved in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, independently of cystine transporter activity.
• Tissue Specificity: Strongly expressed in pancreas, kidney (adult and fetal), skeletal muscle, melanocytes and keratinocytes . Expressed at lower levels in placenta and heart. Weakly expressed in lung, liver and brain (adult and fetal) .; [Isoform 2]: Represents 5-20 % of CTNS transcripts, with the exception of the testis that expresses both isoforms in equal proportions.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Miscellaneous transport and binding events (R-HSA-5223345)
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystinosis	DISXY3VI	Definitive	Autosomal recessive	[1]
Nephropathic cystinosis	DISNAU3W	Definitive	Autosomal recessive	[2]
Juvenile nephropathic cystinosis	DIS1U9XG	Strong	Autosomal recessive	[3]
Ocular cystinosis	DIS91A30	Strong	Autosomal recessive	[3]
Nephropathic infantile cystinosis	DISEEN1S	Supportive	Autosomal recessive	[4]

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 Cystinosin (CTNS).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cystinosin (CTNS).	[9]

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 Cystinosin (CTNS).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cystinosin (CTNS).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cystinosin (CTNS).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cystinosin (CTNS).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cystinosin (CTNS).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cystinosin (CTNS).	[12]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Cystinosin (CTNS).	[13]

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] 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] 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.
• [4] Cystinosis. 2001 Mar 22 [updated 2017 Dec 7]. 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.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] 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.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.