Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAZW5TK)

• DOT Name: Centriole and centriolar satellite protein OFD1 (OFD1)
• Synonyms: Oral-facial-digital syndrome 1 protein; Protein 71-7A
• Gene Name: OFD1
• Related Disease:
  Ciliopathy
  Joubert syndrome 10
  Orofaciodigital syndrome I
  Otopalatodigital syndrome type 1
  Simpson-Golabi-Behmel syndrome type 2
  Autosomal dominant polycystic kidney disease
  Fetal akinesia deformation sequence 1
  Hydrocephalus
  Joubert syndrome
  Orofaciodigital syndrome
  Plasma cell myeloma
  Polycystic kidney disease
  Retinal degeneration
  Retinitis pigmentosa 23
  Megalencephaly
  Movement disorder
  Orofaciodigital syndrome type 6
  Primary ciliary dyskinesia
  Retinitis pigmentosa
  Bardet-Biedl syndrome 4
  Intellectual disability
  Pneumocystis pneumonia
• UniProt ID: OFD1_HUMAN
• Pfam ID: PF16045
• Sequence:
  MMAQSNMFTVADVLSQDELRKKLYQTFKDRGILDTLKTQLRNQLIHELMHPVLSGELQPR
  SISVEGSSLLIGASNSLVADHLQRCGYEYSLSVFFPESGLAKEKVFTMQDLLQLIKINPT
  SSLYKSLVSGSDKENQKGFLMHFLKELAEYHQAKESCNMETQTSSTFNRDSLAEKLQLID
  DQFADAYPQRIKFESLEIKLNEYKREIEEQLRAEMCQKLKFFKDTEIAKIKMEAKKKYEK
  ELTMFQNDFEKACQAKSEALVLREKSTLERIHKHQEIETKEIYAQRQLLLKDMDLLRGRE
  AELKQRVEAFELNQKLQEEKHKSITEALRRQEQNIKSFEETYDRKLKNELLKYQLELKDD
  YIIRTNRLIEDERKNKEKAVHLQEELIAINSKKEELNQSVNRVKELELELESVKAQSLAI
  TKQNHMLNEKVKEMSDYSLLKEEKLELLAQNKLLKQQLEESRNENLRLLNRLAQPAPELA
  VFQKELRKAEKAIVVEHEEFESCRQALHKQLQDEIEHSAQLKAQILGYKASVKSLTTQVA
  DLKLQLKQTQTALENEVYCNPKQSVIDRSVNGLINGNVVPCNGEISGDFLNNPFKQENVL
  ARMVASRITNYPTAWVEGSSPDSDLEFVANTKARVKELQQEAERLEKAFRSYHRRVIKNS
  AKSPLAAKSPPSLHLLEAFKNITSSSPERHIFGEDRVVSEQPQVGTLEERNDVVEALTGS
  AASRLRGGTSSRRLSSTPLPKAKRSLESEMYLEGLGRSHIASPSPCPDRMPLPSPTESRH
  SLSIPPVSSPPEQKVGLYRRQTELQDKSEFSDVDKLAFKDNEEFESSFESAGNMPRQLEM
  GGLSPAGDMSHVDAAAAAVPLSYQHPSVDQKQIEEQKEEEKIREQQVKERRQREERRQSN
  LQEVLERERRELEKLYQERKMIEESLKIKIKKELEMENELEMSNQEIKDKSAHSENPLEK
  YMKIIQQEQDQESADKSSKKMVQEGSLVDTLQSSDKVESLTGFSHEELDDSW
• Function: Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164. Involved in the biogenesis of the cilium, a centriole-associated function. The cilium is a cell surface projection found in many vertebrate cells required to transduce signals important for development and tissue homeostasis. Plays an important role in development by regulating Wnt signaling and the specification of the left-right axis. Only OFD1 localized at the centriolar satellites is removed by autophagy, which is an important step in the ciliogenesis regulation.
• Tissue Specificity: Widely expressed. Expressed in 9 and 14 weeks old embryos in metanephric mesenchyme, oral mucosa, lung, heart, nasal and cranial cartilage, and brain. Expressed in metanephros, brain, tongue, and limb.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Hedgehog 'off' state (R-HSA-5610787)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	X-linked	[1]
Joubert syndrome 10	DIS8MC59	Definitive	X-linked recessive	[2]
Orofaciodigital syndrome I	DIST27XL	Definitive	X-linked	[3]
Otopalatodigital syndrome type 1	DISL8CE9	Definitive	Biomarker	[4]
Simpson-Golabi-Behmel syndrome type 2	DIS1YKCO	Definitive	X-linked recessive	[4]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[5]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Biomarker	[6]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[7]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[8]
Orofaciodigital syndrome	DISSB296	Strong	Genetic Variation	[8]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[9]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[7]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[10]
Retinitis pigmentosa 23	DISNFMES	Strong	X-linked	[11]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[4]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[12]
Orofaciodigital syndrome type 6	DISQY7K4	Supportive	Autosomal recessive	[13]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[14]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[15]
Bardet-Biedl syndrome 4	DISTSZC7	Limited	Biomarker	[16]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[17]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[7]

4 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 Centriole and centriolar satellite protein OFD1 (OFD1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Centriole and centriolar satellite protein OFD1 (OFD1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Centriole and centriolar satellite protein OFD1 (OFD1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Centriole and centriolar satellite protein OFD1 (OFD1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Centriole and centriolar satellite protein OFD1 (OFD1).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Centriole and centriolar satellite protein OFD1 (OFD1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Centriole and centriolar satellite protein OFD1 (OFD1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Centriole and centriolar satellite protein OFD1 (OFD1).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Centriole and centriolar satellite protein OFD1 (OFD1).	[25]

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] OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet. 2009 Oct;85(4):465-81. doi: 10.1016/j.ajhg.2009.09.002.
• [3] Oral-facial-digital syndrome type I: an unusual cause of hereditary cystic kidney disease. Nephrol Dial Transplant. 1997 Jun;12(6):1247-50. doi: 10.1093/ndt/12.6.1247.
• [4] A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006 Sep;120(2):171-8. doi: 10.1007/s00439-006-0210-5. Epub 2006 Jun 17.
• [5] Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease.Clin Genet. 2018 Jul;94(1):125-131. doi: 10.1111/cge.13249. Epub 2018 Apr 11.
• [6] Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies.Prenat Diagn. 2015 Nov;35(11):1073-8. doi: 10.1002/pd.4648. Epub 2015 Aug 3.
• [7] Convergent extension movements and ciliary function are mediated by ofd1, a zebrafish orthologue of the human oral-facial-digital type 1 syndrome gene.Hum Mol Genet. 2009 Jan 15;18(2):289-303. doi: 10.1093/hmg/ddn356. Epub 2008 Oct 29.
• [8] A novel pathogenic variant in OFD1 results in X-linked Joubert syndrome with orofaciodigital features and pituitary aplasia.Am J Med Genet A. 2019 Jun;179(6):1010-1014. doi: 10.1002/ajmg.a.61018. Epub 2019 Mar 20.
• [9] Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.Blood. 2009 Oct 8;114(15):3276-84. doi: 10.1182/blood-2009-04-219436. Epub 2009 Jul 8.
• [10] OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models.PLoS One. 2016 May 19;11(5):e0155860. doi: 10.1371/journal.pone.0155860. eCollection 2016.
• [11] 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.
• [12] Exome sequencing identifies a mutation in OFD1 in a male with Joubert syndrome, orofaciodigital spectrum anomalies and complex polydactyly.Hum Genome Var. 2016 Feb 4;3:15069. doi: 10.1038/hgv.2015.69. eCollection 2016.
• [13] Joubert Syndrome. 2003 Jul 9 [updated 2017 Jun 29]. 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.
• [14] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [15] Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). Hum Mol Genet. 2012 Aug 15;21(16):3647-54. doi: 10.1093/hmg/dds194. Epub 2012 May 22.
• [16] Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators.J Clin Invest. 2014 May;124(5):2059-70. doi: 10.1172/JCI71898. Epub 2014 Apr 1.
• [17] The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia.Mol Genet Genomic Med. 2019 Sep;7(9):e911. doi: 10.1002/mgg3.911. Epub 2019 Aug 1.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [22] 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.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.