Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZX5BP6)

• DOT Name: Ras-related protein Rab-28 (RAB28)
• Gene Name: RAB28
• Related Disease:
  Cone-rod dystrophy 18
  RAB28-related retinopathy
  Cone dystrophy
  Cone-rod dystrophy
  Cone-rod dystrophy 2
• UniProt ID: RAB28_HUMAN
• PDB ID: 2HXS; 3E5H
• Pfam ID: PF00071
• Sequence:
  MSDSEEESQDRQLKIVVLGDGASGKTSLTTCFAQETFGKQYKQTIGLDFFLRRITLPGNL
  NVTLQIWDIGGQTIGGKMLDKYIYGAQGVLLVYDITNYQSFENLEDWYTVVKKVSEESET
  QPLVALVGNKIDLEHMRTIKPEKHLRFCQENGFSSHFVSAKTGDSVFLCFQKVAAEILGI
  KLNKAEIEQSQRVVKADIVNYNQEPMSRTVNPPRSSMCAVQ
• Tissue Specificity: Isoform S is detected in most tissues investigated: cortex, liver, kidney, skeletal muscle, adipose tissue, testis, urothelium, lung, bone marrow and retinal pigment epithelium (RPE). Isoform L 2 is widely and abundantly expressed all tissues. Isoform 3 is highly expressed in heart, lung, bone marrow, retina, brain, and RPE.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 18	DISNEPML	Definitive	Autosomal recessive	[1]
RAB28-related retinopathy	DIS4PHLJ	Definitive	Autosomal recessive	[2]
Cone dystrophy	DIS7SAZZ	Strong	CausalMutation	[1]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[3]
Cone-rod dystrophy 2	DISX2RWY	Limited	Biomarker	[4]

1 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 Ras-related protein Rab-28 (RAB28).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related protein Rab-28 (RAB28).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related protein Rab-28 (RAB28).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-related protein Rab-28 (RAB28).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ras-related protein Rab-28 (RAB28).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras-related protein Rab-28 (RAB28).	[10]

References

• [1] New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy. JAMA Ophthalmol. 2015 Feb;133(2):133-9. doi: 10.1001/jamaophthalmol.2014.4266.
• [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] Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy. Am J Hum Genet. 2013 Jul 11;93(1):110-7. doi: 10.1016/j.ajhg.2013.05.005. Epub 2013 Jun 6.
• [4] Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation.Eur J Hum Genet. 2016 Mar;24(3):459-62. doi: 10.1038/ejhg.2015.144. Epub 2015 Jul 8.
• [5] 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.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.