Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGRQK9V)

• DOT Name: Limb region 1 protein homolog (LMBR1)
• Synonyms: Differentiation-related gene 14 protein
• Gene Name: LMBR1
• Related Disease:
  Acheiropody
  Congenital deformities of limbs
  Congenital heart disease
  Polydactyly
  Polydactyly of a triphalangeal thumb
  Preaxial polydactyly of fingers
  Progressive pseudorheumatoid arthropathy of childhood
  Laurin-Sandrow syndrome
  Obsolete hypoplastic tibiae-postaxial polydactyly syndrome
  Syndactyly type 4
  Triphalangeal thumb-polysyndactyly syndrome
  Syndactyly
• UniProt ID: LMBR1_HUMAN
• Pfam ID: PF04791
• Sequence:
  MEGQDEVSAREQHFHSQVRESTICFLLFAILYVVSYFIITRYKRKSDEQEDEDAIVNRIS
  LFLSTFTLAVSAGAVLLLPFSIISNEILLSFPQNYYIQWLNGSLIHGLWNLASLFSNLCL
  FVLMPFAFFFLESEGFAGLKKGIRARILETLVMLLLLALLILGIVWVASALIDNDAASME
  SLYDLWEFYLPYLYSCISLMGCLLLLLCTPVGLSRMFTVMGQLLVKPTILEDLDEQIYII
  TLEEEALQRRLNGLSSSVEYNIMELEQELENVKTLKTKLERRKKASAWERNLVYPAVMVL
  LLIETSISVLLVACNILCLLVDETAMPKGTRGPGIGNASLSTFGFVGAALEIILIFYLMV
  SSVVGFYSLRFFGNFTPKKDDTTMTKIIGNCVSILVLSSALPVMSRTLGITRFDLLGDFG
  RFNWLGNFYIVLSYNLLFAIVTTLCLVRKFTSAVREELFKALGLHKLHLPNTSRDSETAK
  PSVNGHQKAL
• Function: Putative membrane receptor.
• Tissue Specificity: Widely expressed with strongest expression in heart and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acheiropody	DISC5E7N	Strong	Autosomal recessive	[1]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[2]
Congenital heart disease	DISQBA23	Strong	Genetic Variation	[3]
Polydactyly	DIS25BMZ	Strong	Altered Expression	[3]
Polydactyly of a triphalangeal thumb	DIS7WCFY	Strong	Autosomal dominant	[4]
Preaxial polydactyly of fingers	DISXO6C9	Strong	Genetic Variation	[5]
Progressive pseudorheumatoid arthropathy of childhood	DISBMRIW	Strong	Genetic Variation	[6]
Laurin-Sandrow syndrome	DISOYBC3	Supportive	Autosomal dominant	[7]
Obsolete hypoplastic tibiae-postaxial polydactyly syndrome	DISA748M	Supportive	Autosomal dominant	[8]
Syndactyly type 4	DISMKGLC	Supportive	Autosomal dominant	[7]
Triphalangeal thumb-polysyndactyly syndrome	DIS2V1ZD	Supportive	Autosomal dominant	[9]
Syndactyly	DISZK2BT	Limited	Genetic Variation	[10]

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 Limb region 1 protein homolog (LMBR1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Limb region 1 protein homolog (LMBR1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Limb region 1 protein homolog (LMBR1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Limb region 1 protein homolog (LMBR1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Limb region 1 protein homolog (LMBR1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Limb region 1 protein homolog (LMBR1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Limb region 1 protein homolog (LMBR1).	[16]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Limb region 1 protein homolog (LMBR1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Limb region 1 protein homolog (LMBR1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Limb region 1 protein homolog (LMBR1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Limb region 1 protein homolog (LMBR1).	[20]

References

• [1] Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene. Am J Hum Genet. 2001 Jan;68(1):38-45. doi: 10.1086/316955. Epub 2000 Nov 22.
• [2] A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb.Hum Mutat. 2012 Jul;33(7):1063-6. doi: 10.1002/humu.22097. Epub 2012 May 11.
• [3] Microduplication of 7q36.3 encompassing the SHH longrange regulator (ZRS) in a patient with triphalangeal thumbpolysyndactyly syndrome and congenital heart disease.Mol Med Rep. 2017 Feb;15(2):793-797. doi: 10.3892/mmr.2016.6092. Epub 2016 Dec 29.
• [4] Protecting the macula during eye surgery. J Ark Med Soc. 1976 Oct;73(5):203-4.
• [5] Intrafamilial variability of ZRS-associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing.Clin Genet. 2015 Nov;88(5):479-83. doi: 10.1111/cge.12534. Epub 2015 Jan 6.
• [6] A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud.Genet Med. 2020 Jan;22(1):189-198. doi: 10.1038/s41436-019-0626-7. Epub 2019 Aug 9.
• [7] Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome. Clin Genet. 2014 Oct;86(4):318-25. doi: 10.1111/cge.12352. Epub 2014 Feb 17.
• [8] A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Hum Mutat. 2010 Jan;31(1):81-9. doi: 10.1002/humu.21142.
• [9] A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet. 2008 Jun;45(6):370-5. doi: 10.1136/jmg.2007.055699. Epub 2008 Jan 4.
• [10] Genetic heterogeneity in type III familial cutaneous syndactyly and linkage to chromosome 7q36.Am J Med Genet A. 2013 Jul;161A(7):1579-84. doi: 10.1002/ajmg.a.35956. Epub 2013 May 17.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.