Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO7IV74)

• DOT Name: Armadillo repeat-containing protein 5 (ARMC5)
• Gene Name: ARMC5
• Related Disease:
  ACTH-independent macronodular adrenal hyperplasia 2
  ACTH-independent macronodular adrenal hyperplasia 1
  Adrenal gland hyperfunction
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Congenital adrenal hyperplasia
  Corpus callosum, agenesis of
  Hyperaldosteronism
  Intracranial meningioma
  Malignant tumor of adrenal cortex
  Neoplasm
  Pancreatic tumour
  Primary aldosteronism
  Cushing syndrome due to macronodular adrenal hyperplasia
  High blood pressure
  Meningioma
• UniProt ID: ARMC5_HUMAN
• Sequence:
  MAAAKPTLTDSLSFCLAQLAAAAGEALGGEKDPATNETPLSRALLALRTRHIKAAGGIER
  FRARGGLRPLLALLRRAAAAGSAPSQAGPGSAPSSAASGASSPAPASGPAPSAVSSSSPT
  PPVRLRKTLDLALSILADCCTEGACRTEVRRLGGILPLVTILQCMKTDSIQNRTARALGN
  LAMEPESCGDIHCAGAVPLLVESLTACQDSQCLQSVVRALRNLADSPQHRLALAQQGAVR
  PLAELLATAPDAALTLALVRALLELSRGCSRACAEQLSLGGGLGPLVSLASHPKRAVREG
  TILILANLCAQGLIRPALGNAGGVEVLVDELRQRRDPNGASPTSQQPLVRAVCLLCREAI
  NRARLRDAGGLDLLMGLLRDPRASAWHPRIVAALVGFLYDTGALGRLQALGLVPLLAGQL
  CGEAGEEEEEGREAASWDFPEERTPERAQGGSFRSLRSWLISEGYATGPDDISPDWSPEQ
  CPPEPMEPASPAPTPTSLRAPRTQRTPGRSPAAAIEEPWGREGPALLLLSRFSQAPDPSG
  ALVTGPALYGLLTYVTGAPGPPSPRALRILSRLTCNPACLEAFVRSYGAALLRAWLVLGV
  APDDWPAPRARPTLHSRHRELGERLLQNLTVQAESPFGVGALTHLLLSGSPEDRVACALT
  LPFICRKPSLWRRLLLEQGGLRLLLAALTRPAPHPLFLFFAADSLSCLQDLVSPTVSPAV
  PQAVPMDLDSPSPCLYEPLLGPAPVPAPDLHFLLDSGLQLPAQRAASATASPFFRALLSG
  SFAEAQMDLVPLRGLSPGAAWPVLHHLHGCRGCGAALGPVPPPGQPLLGSEAEEALEAAG
  RFLLPGLEEELEEAVGRIHLGPQGGPESVGEVFRLGRPRLAAHCARWTLGSEQCPRKRGL
  ALVGLVEAAGEEAGPLTEALLAVVMGIELGARVPA
• Function: Involved in fetal development, T-cell function and adrenal gland growth homeostasis. Negatively regulates adrenal cells survival. Plays a role in steroidogenesis, modulates steroidogenic enzymes expression and cortisol production.
• KEGG Pathway: Cushing syndrome (hsa04934)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ACTH-independent macronodular adrenal hyperplasia 2	DIS0KIH4	Definitive	Autosomal dominant	[1]
ACTH-independent macronodular adrenal hyperplasia 1	DISH2YV8	Strong	Biomarker	[2]
Adrenal gland hyperfunction	DISPP4ZK	Strong	Genetic Variation	[3]
Adrenocortical carcinoma	DISZF4HX	Strong	Biomarker	[4]
Aplasia cutis congenita	DISMDAYM	Strong	Biomarker	[4]
Congenital adrenal hyperplasia	DISG873W	Strong	Genetic Variation	[5]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[4]
Hyperaldosteronism	DIS3WGAL	Strong	Biomarker	[6]
Intracranial meningioma	DISD09EF	Strong	Genetic Variation	[7]
Malignant tumor of adrenal cortex	DIS7E0I8	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[8]
Pancreatic tumour	DIS3U0LK	Strong	Genetic Variation	[7]
Primary aldosteronism	DISOEFNH	moderate	Genetic Variation	[3]
Cushing syndrome due to macronodular adrenal hyperplasia	DISBVOYU	Supportive	Autosomal dominant	[9]
High blood pressure	DISY2OHH	Limited	Biomarker	[10]
Meningioma	DISPT4TG	Limited	Altered Expression	[11]

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 Armadillo repeat-containing protein 5 (ARMC5).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Armadillo repeat-containing protein 5 (ARMC5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Armadillo repeat-containing protein 5 (ARMC5).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Armadillo repeat-containing protein 5 (ARMC5).	[15]

References

• [1] 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.
• [2] Whole-genome sequencing revealed armadillo repeat containing 5 (ARMC5) mutation in a Chinese family with ACTH-independent macronodular adrenal hyperplasia.Endocr J. 2018 Mar 28;65(3):269-279. doi: 10.1507/endocrj.EJ17-0317. Epub 2017 Dec 27.
• [3] ARMC5 mutations in familial and sporadic primary bilateral macronodular adrenal hyperplasia.PLoS One. 2018 Jan 25;13(1):e0191602. doi: 10.1371/journal.pone.0191602. eCollection 2018.
• [4] An update on adrenal endocrinology: significant discoveries in the last 10years and where the field is heading in the next decade.Hormones (Athens). 2018 Dec;17(4):479-490. doi: 10.1007/s42000-018-0072-y. Epub 2018 Nov 19.
• [5] A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.Endocrine. 2017 Mar;55(3):959-968. doi: 10.1007/s12020-016-0956-z. Epub 2016 Apr 19.
• [6] ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia.J Clin Endocrinol Metab. 2014 Sep;99(9):E1784-92. doi: 10.1210/jc.2014-1265. Epub 2014 Jun 6.
• [7] Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma.J Clin Endocrinol Metab. 2015 Jan;100(1):E119-28. doi: 10.1210/jc.2014-2648.
• [8] A novel germline ARMC5 mutation in a patient with bilateral macronodular adrenal hyperplasia: a case report.BMC Med Genet. 2018 Mar 27;19(1):49. doi: 10.1186/s12881-018-0564-2.
• [9] ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med. 2013 Nov 28;369(22):2105-14. doi: 10.1056/NEJMoa1304603.
• [10] ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.J Am Heart Assoc. 2019 Jul 16;8(14):e012508. doi: 10.1161/JAHA.119.012508. Epub 2019 Jul 3.
• [11] Analysis of ARMC5 expression in human tissues.Mol Cell Endocrinol. 2017 Feb 5;441:140-145. doi: 10.1016/j.mce.2016.08.018. Epub 2016 Aug 24.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.