Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6DAHNF)

• DOT Name: Myocilin (MYOC)
• Synonyms: Myocilin 55 kDa subunit; Trabecular meshwork-induced glucocorticoid response protein
• Gene Name: MYOC
• Related Disease:
  Glaucoma 1, open angle, A
  Open-angle glaucoma
  Advanced cancer
  Al-Raqad syndrome
  Amyloidosis
  Angle-closure glaucoma
  Axenfeld-Rieger syndrome
  Blindness
  Cardiac failure
  Congestive heart failure
  Glomerulosclerosis
  Hereditary glaucoma
  Nephrotic syndrome
  Optic nerve disorder
  Primary angle-closure glaucoma
  Refractive error
  Schwannoma
  Congenital glaucoma
  Juvenile open angle glaucoma
  Disorder of orbital region
  Glaucoma 3A
  High blood pressure
  Parkinson disease
• UniProt ID: MYOC_HUMAN
• PDB ID: 4WXQ; 4WXS; 4WXU; 6OU0; 6OU1; 6OU2; 6OU3; 6PKD; 6PKE; 6PKF; 7SIB; 7SIJ; 7SJT; 7SJU; 7SJV; 7SJW; 7SKD; 7SKE; 7SKF; 7SKG; 7T8D
• Pfam ID: PF02191
• Sequence:
  MRFFCARCCSFGPEMPAVQLLLLACLVWDVGARTAQLRKANDQSGRCQYTFSVASPNESS
  CPEQSQAMSVIHNLQRDSSTQRLDLEATKARLSSLESLLHQLTLDQAARPQETQEGLQRE
  LGTLRRERDQLETQTRELETAYSNLLRDKSVLEEEKKRLRQENENLARRLESSSQEVARL
  RRGQCPQTRDTARAVPPGSREVSTWNLDTLAFQELKSELTEVPASRILKESPSGYLRSGE
  GDTGCGELVWVGEPLTLRTAETITGKYGVWMRDPKPTYPYTQETTWRIDTVGTDVRQVFE
  YDLISQFMQGYPSKVHILPRPLESTGAVVYSGSLYFQGAESRTVIRYELNTETVKAEKEI
  PGAGYHGQFPYSWGGYTDIDLAVDEAGLWVIYSTDEAKGAIVLSKLNPENLELEQTWETN
  IRKQSVANAFIICGTLYTVSSYTSADATVNFAYDTGTGISKTLTIPFKNRYKYSSMIDYN
  PLEKKLFAWDNLNMVTYDIKLSKM
• Function: Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.
• Tissue Specificity: Detected in aqueous humor . Detected in the eye (at protein level) . Widely expressed. Highly expressed in various types of muscle, ciliary body, papillary sphincter, skeletal muscle, heart, and bone marrow-derived mesenchymal stem cells. Expressed predominantly in the retina. In normal eyes, found in the inner uveal meshwork region and the anterior portion of the meshwork. In contrast, in many glaucomatous eyes, it is found in more regions of the meshwork and seems to be expressed at higher levels than in normal eyes, regardless of the type or clinical severity of glaucoma. The myocilin 35 kDa fragment is detected in aqueous humor and to a lesser extent in iris and ciliary body.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma 1, open angle, A	DISLCMIU	Definitive	Autosomal dominant	[1]
Open-angle glaucoma	DISSZEE8	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Al-Raqad syndrome	DISR2J8Q	Strong	Genetic Variation	[4]
Amyloidosis	DISHTAI2	Strong	Biomarker	[5]
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[6]
Axenfeld-Rieger syndrome	DIS6XY4L	Strong	Genetic Variation	[4]
Blindness	DISTIM10	Strong	Genetic Variation	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Glomerulosclerosis	DISJF20Z	Strong	Altered Expression	[9]
Hereditary glaucoma	DISJYSR1	Strong	Biomarker	[10]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[11]
Optic nerve disorder	DISSOQM8	Strong	Genetic Variation	[12]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Genetic Variation	[6]
Refractive error	DISWNEQ1	Strong	Biomarker	[13]
Schwannoma	DISTTVLA	moderate	Altered Expression	[14]
Congenital glaucoma	DISHN3GO	Supportive	Autosomal dominant	[15]
Juvenile open angle glaucoma	DISZ43T5	Supportive	Autosomal dominant	[15]
Disorder of orbital region	DISH0ECJ	Limited	Genetic Variation	[16]
Glaucoma 3A	DISHJWKA	Limited	Autosomal dominant	[17]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[18]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Myocilin (MYOC).	[20]

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 affects the methylation of Myocilin (MYOC).	[21]

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] 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] Cystatin a, a potential common link for mutant myocilin causative glaucoma.PLoS One. 2012;7(5):e36301. doi: 10.1371/journal.pone.0036301. Epub 2012 May 15.
• [4] Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population.Mol Vis. 2013 Aug 4;19:1707-22. Print 2013.
• [5] Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma.Hum Mol Genet. 2014 Dec 15;23(24):6470-80. doi: 10.1093/hmg/ddu367. Epub 2014 Jul 15.
• [6] Haplotype analysis of association of the MYOC gene with primary angle-closure glaucoma in a Han Chinese population.Genet Test Mol Biomarkers. 2015 Jan;19(1):3-8. doi: 10.1089/gtmb.2014.0130.
• [7] Simulations and Experiments Delineate Amyloid Fibrilization by Peptides Derived from Glaucoma-Associated Myocilin.J Phys Chem B. 2018 Jun 7;122(22):5845-5850. doi: 10.1021/acs.jpcb.8b03000. Epub 2018 May 21.
• [8] YiQiFuMai powder injection ameliorates chronic heart failure through cross-talk between adipose tissue and cardiomyocytes via up-regulation of circulating adipokine omentin.Biomed Pharmacother. 2019 Nov;119:109418. doi: 10.1016/j.biopha.2019.109418. Epub 2019 Sep 7.
• [9] Myocilin is expressed in the glomerulus of the kidney and induced in mesangioproliferative glomerulonephritis.Kidney Int. 2005 Jan;67(1):140-51. doi: 10.1111/j.1523-1755.2005.00064.x.
• [10] Antibodies Used to Detect Glaucoma-Associated Myocilin: More or Less Than Meets the Eye?.Invest Ophthalmol Vis Sci. 2019 May 1;60(6):2034-2037. doi: 10.1167/iovs.19-26843.
• [11] Increased expression of olfactomedin-1 and myocilin in podocytes during puromycin aminonucleoside nephrosis.Nephrol Dial Transplant. 2011 Jan;26(1):83-92. doi: 10.1093/ndt/gfq366. Epub 2010 Jun 30.
• [12] The glaucoma-associated olfactomedin domain of myocilin is a novel calcium binding protein.J Biol Chem. 2012 Dec 21;287(52):43370-7. doi: 10.1074/jbc.M112.408906. Epub 2012 Nov 5.
• [13] Phenotypic differences between familial versus non-familial Juvenile onset open angle glaucoma patients.Ophthalmic Genet. 2018 Jan-Feb;39(1):63-67. doi: 10.1080/13816810.2017.1368088. Epub 2017 Sep 14.
• [14] Secreted glycoprotein myocilin is a component of the myelin sheath in peripheral nerves.Glia. 2003 Aug;43(2):128-40. doi: 10.1002/glia.10233.
• [15] Genetics of primary glaucoma. Curr Opin Ophthalmol. 2011 Sep;22(5):347-55. doi: 10.1097/ICU.0b013e32834922d2.
• [16] How does a protein's structure spell the difference between health and disease? Our journey to understand glaucoma-associated myocilin.PLoS Biol. 2019 Apr 22;17(4):e3000237. doi: 10.1371/journal.pbio.3000237. eCollection 2019 Apr.
• [17] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [18] Analyses of Sequence Variants in the MYOC Gene and of Single Nucleotide Polymorphisms in the NR3C1 and FKBP5 Genes in Corticosteroid-Induced Ocular Hypertension.Ophthalmic Genet. 2015;36(4):299-302. doi: 10.3109/13816810.2013.879598. Epub 2015 Aug 28.
• [19] Myocilin variants in Indian patients with open-angle glaucoma.Arch Ophthalmol. 2007 Jun;125(6):823-9. doi: 10.1001/archopht.125.6.823.
• [20] Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure. Arch Ophthalmol. 2008 Dec;126(12):1700-6. doi: 10.1001/archophthalmol.2008.512.
• [21] 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.