Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLM6717)

• DOT Name: pre-mRNA splicing regulator USH1G
• Synonyms: Scaffold protein containing ankyrin repeats and SAM domain; Usher syndrome type-1G protein
• Gene Name: USH1G
• Related Disease:
  Usher syndrome type 1
  Usher syndrome type 1G
  Nonsyndromic genetic hearing loss
• UniProt ID: USH1G_HUMAN
• PDB ID: 2L7T; 3K1R; 3PVL
• Pfam ID: PF12796 ; PF00536
• Sequence:
  MNDQYHRAARDGYLELLKEATRKELNAPDEDGMTPTLWAAYHGNLESLRLIVSRGGDPDK
  CDIWGNTPLHLAASNGHLHCLSFLVSFGANIWCLDNDYHTPLDMAAMKGHMECVRYLDSI
  AAKQSSLNPKLVGKLKDKAFREAERRIRECAKLQRRHHERMERRYRRELAERSDTLSFSS
  LTSSTLSRRLQHLALGSHLPYSQATLHGTARGKTKMQKKLERRKQGGEGTFKVSEDGRKS
  ARSLSGLQLGSDVMFVRQGTYANPKEWGRAPLRDMFLSDEDSVSRATLAAEPAHSEVSTD
  SGHDSLFTRPGLGTMVFRRNYLSSGLHGLGREDGGLDGVGAPRGRLQSSPSLDDDSLGSA
  NSLQDRSCGEELPWDELDLGLDEDLEPETSPLETFLASLHMEDFAALLRQEKIDLEALML
  CSDLDLRSISVPLGPRKKILGAVRRRRQAMERPPALEDTEL
• Function: Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assembly of the pre-catalytic spliceosome on target pre-mRNAs. May also participate in recycling of snRNPs back to Cajal bodies during splicing. Plays a role in regulating MAGI2-mediated endocytosis. Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal development and maintenance of cochlear hair cell bundles. Required for normal hearing.
• Tissue Specificity: Expressed in vestibule of the inner ear, eye and small intestine.
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Usher syndrome type 1	DISR29E4	Definitive	Autosomal recessive	[1]
Usher syndrome type 1G	DISZFLFA	Definitive	Autosomal recessive	[2]
Nonsyndromic genetic hearing loss	DISZX61P	Disputed	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of pre-mRNA splicing regulator USH1G.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of pre-mRNA splicing regulator USH1G.	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of pre-mRNA splicing regulator USH1G.	[5]

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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [5] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.