Details of Drug Off-Target (DOT)

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

• DOT Name: Lebercilin (LCA5)
• Synonyms: Leber congenital amaurosis 5 protein
• Gene Name: LCA5
• Related Disease:
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Inherited retinal dystrophy
  LCA5-related retinopathy
  Leber congenital amaurosis 5
  Joubert syndrome
  Pathologic nystagmus
  Respiratory disease
  Usher syndrome
  Leber congenital amaurosis 1
  Leber congenital amaurosis
  Severe early-childhood-onset retinal dystrophy
  Blindness
  Ciliopathy
  Retinitis pigmentosa
• UniProt ID: LCA5_HUMAN
• Pfam ID: PF15619
• Sequence:
  MGERAGSPGTDQERKAGKHHYSYLSDFETPQSSGRSSLVSSSPASVRRKNPKRQTSDGQV
  HHQAPRKPSPKGLPNRKGVRVGFRSQSLNREPLRKDTDLVTKRILSARLLKINELQNEVS
  ELQVKLAELLKENKSLKRLQYRQEKALNKFEDAENEISQLIFRHNNEITALKERLRKSQE
  KERATEKRVKDTESELFRTKFSLQKLKEISEARHLPERDDLAKKLVSAELKLDDTERRIK
  ELSKNLELSTNSFQRQLLAERKRAYEAHDENKVLQKEVQRLYHKLKEKERELDIKNIYSN
  RLPKSSPNKEKELALRKNAACQSDFADLCTKGVQTMEDFKPEEYPLTPETIMCYENKWEE
  PGHLTLDLQSQKQDRHGEAGILNPIMEREEKFVTDEELHVVKQEVEKLEDEWEREELDKK
  QKEKASLLEREEKPEWETGRYQLGMYPIQNMDKLQGEEEERLKREMLLAKLNEIDRELQD
  SRNLKYPVLPLLPDFESKLHSPERSPKTYRFSESSERLFNGHHLQDISFSTPKGEGQNSG
  NVRSPASPNEFAFGSYVPSFAKTSERSNPFSQKSSFLDFQRNSMEKLSKDGVDLITRKEK
  KANLMEQLFGASGSSTISSKSSDPNSVASSKGDIDPLNFLPGNKGSRDQEHDEDEGFFLS
  EGRSFNPNRHRLKHADDKPAVKAADSVEDEIEEVALR
• Function: Involved in intraflagellar protein (IFT) transport in photoreceptor cilia.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy	DISY9RWN	Definitive	Genetic Variation	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	CausalMutation	[2]
LCA5-related retinopathy	DISCSXVI	Definitive	Autosomal recessive	[3]
Leber congenital amaurosis 5	DISN2JPY	Definitive	Autosomal recessive	[4]
Joubert syndrome	DIS7P5CO	Strong	Biomarker	[5]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[6]
Respiratory disease	DISGGAGJ	Strong	Genetic Variation	[7]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[8]
Leber congenital amaurosis 1	DISY2B33	moderate	Biomarker	[1]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[9]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Supportive	Autosomal recessive	[10]
Blindness	DISTIM10	Limited	Genetic Variation	[7]
Ciliopathy	DIS10G4I	Limited	Genetic Variation	[11]
Retinitis pigmentosa	DISCGPY8	Limited	Biomarker	[6]

2 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 Lebercilin (LCA5).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lebercilin (LCA5).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lebercilin (LCA5).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lebercilin (LCA5).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lebercilin (LCA5).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lebercilin (LCA5).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Lebercilin (LCA5).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Lebercilin (LCA5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lebercilin (LCA5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lebercilin (LCA5).	[17]

References

• [1] Knocking out lca5 in zebrafish causes cone-rod dystrophy due to impaired outer segment protein trafficking.Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2694-2705. doi: 10.1016/j.bbadis.2019.07.009. Epub 2019 Jul 23.
• [2] Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.Genet Med. 2015 Apr;17(4):253-261. doi: 10.1038/gim.2014.172. Epub 2014 Nov 20.
• [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] 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] 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.
• [6] Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.Ophthalmology. 2014 Jan;121(1):399-407. doi: 10.1016/j.ophtha.2013.08.028. Epub 2013 Oct 18.
• [7] Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis.Mol Vis. 2008 Mar 10;14:481-6.
• [8] Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein.Hum Mol Genet. 2009 Jan 1;18(1):51-64. doi: 10.1093/hmg/ddn312. Epub 2008 Sep 30.
• [9] Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nat Genet. 2007 Jul;39(7):889-95. doi: 10.1038/ng2066. Epub 2007 Jun 3.
• [10] Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. Hum Mutat. 2013 Nov;34(11):1537-1546. doi: 10.1002/humu.22398. Epub 2013 Sep 17.
• [11] Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness.Mol Ther. 2018 Jun 6;26(6):1581-1593. doi: 10.1016/j.ymthe.2018.03.015. Epub 2018 Mar 21.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] 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.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.