Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYHUXC1)

• DOT Name: Transmembrane protein 127 (TMEM127)
• Gene Name: TMEM127
• Related Disease:
  Clear cell renal carcinoma
  Hereditary pheochromocytoma-paraganglioma
  Intellectual disability
  Pheochromocytoma
  Advanced cancer
  Fatty liver disease
  Kidney neoplasm
  Malignant mesothelioma
  Paraganglioma
  Von hippel-lindau disease
  Renal cell carcinoma
  Hereditary neoplastic syndrome
  Neuroendocrine neoplasm
• UniProt ID: TM127_HUMAN
• Pfam ID: PF20517
• Sequence:
  MYAPGGAGLPGGRRRRSPGGSALPKQPERSLASALPGALSITALCTALAEPAWLHIHGGT
  CSRQELGVSDVLGYVHPDLLKDFCMNPQTVLLLRVIAAFCFLGILCSLSAFLLDVFGPKH
  PALKITRRYAFAHILTVLQCATVIGFSYWASELILAQQQQHKKYHGSQVYVTFAVSFYLV
  AGAGGASILATAANLLRHYPTEEEEQALELLSEMEENEPYPAEYEVINQFQPPPAYTP
• Function: Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1. May act as a tumor suppressor.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Definitive	Genetic Variation	[1]
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Definitive	Autosomal dominant	[2]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[3]
Pheochromocytoma	DIS56IFV	Definitive	Autosomal dominant	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[5]
Malignant mesothelioma	DISTHJGH	Strong	Altered Expression	[7]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[8]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[5]
Renal cell carcinoma	DISQZ2X8	Moderate	Autosomal dominant	[9]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	Genetic Variation	[10]
Neuroendocrine neoplasm	DISNPLOO	Limited	Genetic Variation	[11]

7 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 Transmembrane protein 127 (TMEM127).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane protein 127 (TMEM127).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 127 (TMEM127).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane protein 127 (TMEM127).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transmembrane protein 127 (TMEM127).	[16]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Transmembrane protein 127 (TMEM127).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transmembrane protein 127 (TMEM127).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane protein 127 (TMEM127).	[19]

References

• [1] Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.J Clin Endocrinol Metab. 2017 Nov 1;102(11):4013-4022. doi: 10.1210/jc.2017-00562.
• [2] 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.
• [3] Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.Clin Genet. 2018 May;93(5):1049-1056. doi: 10.1111/cge.13202. Epub 2018 Mar 23.
• [4] 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.
• [5] Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel-Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127).Endocr Pathol. 2017 Sep;28(3):253-268. doi: 10.1007/s12022-017-9489-0.
• [6] The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner.Nat Commun. 2019 Oct 17;10(1):4720. doi: 10.1038/s41467-019-12661-0.
• [7] Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.J Clin Oncol. 2018 Oct 1;36(28):2863-2871. doi: 10.1200/JCO.2018.78.5204. Epub 2018 Aug 16.
• [8] Concurrent heterozygous Von-Hippel-Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis.J Hypertens. 2020 Feb;38(2):340-346. doi: 10.1097/HJH.0000000000002253.
• [9] 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.
• [10] Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome.Pathol Oncol Res. 2016 Oct;22(4):673-9. doi: 10.1007/s12253-016-0050-0. Epub 2016 Mar 9.
• [11] Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma.Hum Mol Genet. 2011 Oct 15;20(20):3974-85. doi: 10.1093/hmg/ddr324. Epub 2011 Jul 22.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.