Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ADI7Q)

• DOT Name: Clarin-1 (CLRN1)
• Synonyms: Usher syndrome type-3 protein
• Gene Name: CLRN1
• Related Disease:
  Usher syndrome type 3
  Usher syndrome type 3A
  Alopecia
  Blindness
  Cataract
  Deafness
  Ear disease
  Retinitis pigmentosa 1
  Retinitis pigmentosa 61
  Sensorineural hearing loss disorder
  Trichohepatoenteric syndrome
  Retinitis punctata albescens
  Retinitis pigmentosa
  Usher syndrome type 1C
  Usher syndrome
• UniProt ID: CLRN1_HUMAN
• Sequence:
  MPSQQKKIIFCMAGVFSFACALGVVTALGTPLWIKATVLCKTGALLVNASGQELDKFMGE
  MQYGLFHGEGVRQCGLGARPFRFSFFPDLLKAIPVSIHVNVILFSAILIVLTMVGTAFFM
  YNAFGKPFETLHGPLGLYLLSFISGSCGCLVMILFASEVKIHHLSEKIANYKEGTYVYKT
  QSEKYTTSFWVIFFCFFVHFLNGLLIRLAGFQFPFAKSKDAETTNVAADLMY
• Function: May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina.
• Tissue Specificity: Widely expressed. Found in the retina.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Usher syndrome type 3	DISRAL84	Definitive	Autosomal recessive	[1]
Usher syndrome type 3A	DISHYN3T	Definitive	Autosomal recessive	[2]
Alopecia	DIS37HU4	Strong	Genetic Variation	[3]
Blindness	DISTIM10	Strong	Biomarker	[4]
Cataract	DISUD7SL	Strong	Genetic Variation	[5]
Deafness	DISKCLH4	Strong	Genetic Variation	[6]
Ear disease	DISCL1WZ	Strong	Genetic Variation	[7]
Retinitis pigmentosa 1	DISSLQPP	Strong	Biomarker	[8]
Retinitis pigmentosa 61	DISUGKOX	Strong	Autosomal recessive	[9]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[10]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[11]
Retinitis punctata albescens	DISVJAI4	moderate	Genetic Variation	[12]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[13]
Usher syndrome type 1C	DIS4U70X	Disputed	Biomarker	[14]
Usher syndrome	DIS9YIS7	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Clarin-1 (CLRN1).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Clarin-1 (CLRN1).	[16]

2 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 Clarin-1 (CLRN1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Clarin-1 (CLRN1).	[18]

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] A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula. Sci Rep. 2017 May 3;7(1):1411. doi: 10.1038/s41598-017-01577-8.
• [3] Zebrafish Models for the Mechanosensory Hair Cell Dysfunction in Usher Syndrome 3 Reveal That Clarin-1 Is an Essential Hair Bundle Protein.J Neurosci. 2015 Jul 15;35(28):10188-201. doi: 10.1523/JNEUROSCI.1096-15.2015.
• [4] Identification of whirlin domains interacting with espin: A study of the mechanism of Usher syndrome typeII.Mol Med Rep. 2019 Dec;20(6):5111-5117. doi: 10.3892/mmr.2019.10728. Epub 2019 Oct 7.
• [5] Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3.Orphanet J Rare Dis. 2012 Sep 2;7:59. doi: 10.1186/1750-1172-7-59.
• [6] Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
• [7] The mechanosensory structure of the hair cell requires clarin-1, a protein encoded by Usher syndrome III causative gene.J Neurosci. 2012 Jul 11;32(28):9485-98. doi: 10.1523/JNEUROSCI.0311-12.2012.
• [8] Usher syndrome type III: revised genomic structure of the USH3 gene and identification of novel mutations.Am J Hum Genet. 2002 Sep;71(3):607-17. doi: 10.1086/342098. Epub 2002 Jul 16.
• [9] CLRN1 mutations cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2011 Jul;118(7):1444-8. doi: 10.1016/j.ophtha.2010.10.047. Epub 2011 Feb 18.
• [10] AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.PLoS One. 2016 Feb 16;11(2):e0148874. doi: 10.1371/journal.pone.0148874. eCollection 2016.
• [11] Usher syndrome: from genetics to pathogenesis.Annu Rev Genomics Hum Genet. 2001;2:271-97. doi: 10.1146/annurev.genom.2.1.271.
• [12] Usher syndrome type III can mimic other types of Usher syndrome.Ann Otol Rhinol Laryngol. 2003 Jun;112(6):525-30. doi: 10.1177/000348940311200608.
• [13] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. 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] Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome.J Clin Invest. 2018 Aug 1;128(8):3382-3401. doi: 10.1172/JCI94351. Epub 2018 Jul 9.
• [15] Clarin-1 expression in adult mouse and human retina highlights a role of Mller glia in Usher syndrome.J Pathol. 2020 Feb;250(2):195-204. doi: 10.1002/path.5360. Epub 2019 Dec 4.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] 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.
• [18] 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.