Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0MZER2)

• DOT Name: LisH domain-containing protein ARMC9 (ARMC9)
• Synonyms: Armadillo repeat-containing protein 9; Melanoma/melanocyte-specific tumor antigen KU-MEL-1; NS21
• Gene Name: ARMC9
• Related Disease:
  Diabetic retinopathy
  Ependymoma
  Glycogen storage disease type II
  Joubert syndrome 30
  Malaria
  Autoimmune disease
  Behcet disease
  Ciliopathy
  Constipation
  Currarino triad
  Depression
  Head and neck cancer
  Head and neck carcinoma
  Intellectual disability
  Joubert syndrome 1
  Melanoma
  Neoplasm
  Polydactyly
  Joubert syndrome
  Mucopolysaccharidosis type 3A
  Stroke
• UniProt ID: ARMC9_HUMAN
• Pfam ID: PF21050 ; PF21051
• Sequence:
  MGDILAHESELLGLVKEYLDFAEFEDTLKTFSKECKIKGKPLCKTVGGSFRDSKSLTIQK
  DLVAAFDNGDQKVFFDLWEEHISSSIRDGDSFAQKLEFYLHIHFAIYLLKYSVGRPDKEE
  LDEKISYFKTYLETKGAALSQTTEFLPFYALPFVPNPMVHPSFKELFQDSWTPELKLKLI
  KFLALISKASNTPKLLTIYKENGQSNKEILQQLHQQLVEAERRSVTYLKRYNKIQADYHN
  LIGVTAELVDSLEATVSGKMITPEYLQSVCVRLFSNQMRQSLAHSVDFTRPGTASTMLRA
  SLAPVKLKDVPLLPSLDYEKLKKDLILGSDRLKAFLLQALRWRLTTSHPGEQRETVLQAY
  ISNDLLDCYSHNQRSVLQLLHSTSDVVRQYMARLINAFASLAEGRLYLAQNTKVLQMLEG
  RLKEEDKDIITRENVLGALQKFSLRRPLQTAMIQDGLIFWLVDVLKDPDCLSDYTLEYSV
  ALLMNLCLRSTGKNMCAKVAGLVLKVLSDLLGHENHEIQPYVNGALYSILSVPSIREEAR
  AMGMEDILRCFIKEGNAEMIRQIEFIIKQLNSEELPDGVLESDDDEDEDDEEDHDIMEAD
  LDKDELIQPQLGELSGEKLLTTEYLGIMTNTGKTRRKGLANVQWSGDEPLQRPVTPGGHR
  NGYPVVEDQHTPPQTAQHARNGHPQALPAAHEAVYREGKPSTPESCVSSSSAIIAKPGEW
  LPRGRQEEPRPAPTGTPRQPREAPQDPGNGVTTRECASAFTCKPRAPCTPEMLDWNPPKA
  KASVLAPLFSSCGPQQASRPGSTASSTRGLPSSQSHRK
• Function: Involved in ciliogenesis. It is required for appropriate acetylation and polyglutamylation of ciliary microtubules, and regulation of cilium length. Acts as a positive regulator of hedgehog (Hh)signaling. May participate in the trafficking and/or retention of GLI2 and GLI3 proteins at the ciliary tip.
• Tissue Specificity: Strongly expressed in most melanomas and melanocytes. Weakly expressed in the testis.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Definitive	Genetic Variation	[1]
Ependymoma	DISUMRNZ	Definitive	Biomarker	[2]
Glycogen storage disease type II	DISXZPBC	Definitive	Biomarker	[1]
Joubert syndrome 30	DISTEIS2	Definitive	Autosomal recessive	[3]
Malaria	DISQ9Y50	Definitive	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Behcet disease	DISSYMBS	Strong	Biomarker	[6]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[7]
Constipation	DISRQXWI	Strong	Biomarker	[8]
Currarino triad	DISKH37P	Strong	Biomarker	[9]
Depression	DIS3XJ69	Strong	Genetic Variation	[10]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[11]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[11]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[12]
Melanoma	DIS1RRCY	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[7]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[12]
Mucopolysaccharidosis type 3A	DIS2TLNF	Limited	Biomarker	[13]
Stroke	DISX6UHX	Limited	Biomarker	[14]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	LisH domain-containing protein ARMC9 (ARMC9) increases the Metabolic disorder ADR of Chlorothiazide.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of LisH domain-containing protein ARMC9 (ARMC9).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of LisH domain-containing protein ARMC9 (ARMC9).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LisH domain-containing protein ARMC9 (ARMC9).	[27]

11 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 LisH domain-containing protein ARMC9 (ARMC9).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[22]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[23]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of LisH domain-containing protein ARMC9 (ARMC9).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of LisH domain-containing protein ARMC9 (ARMC9).	[28]

References

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• [2] Genetic differences on intracranial versus spinal cord ependymal tumors: a meta-analysis of genetic researches.Eur Spine J. 2016 Dec;25(12):3942-3951. doi: 10.1007/s00586-016-4745-4. Epub 2016 Sep 16.
• [3] 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.
• [4] The Armadillo repeat protein PF16 is essential for flagellar structure and function in Plasmodium male gametes.PLoS One. 2010 Sep 23;5(9):e12901. doi: 10.1371/journal.pone.0012901.
• [5] Tumor antigens isolated from a patient with vitiligo and T-cell-infiltrated melanoma.Cancer Res. 2001 Nov 1;61(21):7900-7.
• [6] Frequent immune response to a melanocyte specific protein KU-MEL-1 in patients with Vogt-Koyanagi-Harada disease.Br J Ophthalmol. 2006 Jun;90(6):773-7. doi: 10.1136/bjo.2005.086520. Epub 2006 Feb 15.
• [7] Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly.Am J Med Genet A. 2018 Jan;176(1):34-40. doi: 10.1002/ajmg.a.38537. Epub 2017 Nov 21.
• [8] Examining Balloon Expulsion Testing as an Office-Based, Screening Test for Dyssynergic Defecation: A Systematic Review and Meta-Analysis.Am J Gastroenterol. 2018 Nov;113(11):1613-1620. doi: 10.1038/s41395-018-0230-5. Epub 2018 Aug 31.
• [9] The Currarino triad: What pediatric surgeons need to know.J Pediatr Surg. 2017 Aug;52(8):1260-1268. doi: 10.1016/j.jpedsurg.2016.12.010. Epub 2016 Dec 27.
• [10] Modeling trait depression amplifies the effect of childbearing on postpartum depression.J Affect Disord. 2017 Dec 1;223:69-75. doi: 10.1016/j.jad.2017.07.017. Epub 2017 Jul 13.
• [11] Prophylactic NS-21 maintains the skin moisture but does not reduce the severity of radiation dermatitis in patients with head and neck cancer: a randomized control trial.Radiat Oncol. 2019 May 30;14(1):90. doi: 10.1186/s13014-019-1302-4.
• [12] Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish. Am J Hum Genet. 2017 Jul 6;101(1):23-36. doi: 10.1016/j.ajhg.2017.05.010. Epub 2017 Jun 15.
• [13] Genetic manipulation of murine embryonic stem cells with enhanced green fluorescence protein and sulfatase-modifying factor I genes.Cytotherapy. 2010 May;12(3):400-7. doi: 10.3109/14653241003695026.
• [14] Comparison of proximal versus distal upper-limb robotic rehabilitation on motor performance after stroke: a cluster controlled trial.Sci Rep. 2018 Feb 1;8(1):2091. doi: 10.1038/s41598-018-20330-3.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [24] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [25] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] 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.
• [28] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [29] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.