Details of Drug Off-Target (DOT)

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

• DOT Name: Leucine-rich melanocyte differentiation-associated protein (LRMDA)
• Gene Name: LRMDA
• Related Disease:
  Atrial fibrillation
  Chromosomal disorder
  Chronic obstructive pulmonary disease
  Cleft palate
  Drug dependence
  Isolated cleft palate
  Non-insulin dependent diabetes
  Oculocutaneous albinism type 7
  Substance abuse
  Substance dependence
  Systemic sclerosis
  Albinism
  Breast cancer
  Breast carcinoma
  Familial atrial fibrillation
  X-linked recessive ocular albinism
  Alopecia
  Androgenetic alopecia
  Baldness, male pattern
• UniProt ID: LRMDA_HUMAN
• Pfam ID: PF14580
• Sequence:
  MEKYLSLSGNHSSNKRSLEGLSAFRSLEELILDNNQLGDDLVLPGLPRLHTLTLNKNRIT
  DLENLLDHLAEVTPALEYLSLLGNVACPNELVSLEKDEEDYKRYRCFVLYKLPNLKFLDA
  QKVTRQEREEALVRGVFMKVVKPKASSEDVASSPERHYTPLPSASRELTSHQGVLGKCRY
  VYYGKNSEGNRFIRDDQL
• Function: Required for melanocyte differentiation.
• Tissue Specificity: In the embryo, expressed in melanoblasts. In the fetus, expressed in melanocytes. Not detected in retinal pigment epithelial cells.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[3]
Cleft palate	DIS6G5TF	Strong	Biomarker	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Oculocutaneous albinism type 7	DISVVH65	Strong	Autosomal recessive	[7]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[8]
Albinism	DIS5D82I	moderate	Genetic Variation	[7]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[9]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[9]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
X-linked recessive ocular albinism	DISI9S32	moderate	Genetic Variation	[10]
Alopecia	DIS37HU4	Limited	Genetic Variation	[11]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[12]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Leucine-rich melanocyte differentiation-associated protein (LRMDA) increases the Acute lymphocytic leukaemia ADR of Aspirin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[20]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[22]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Leucine-rich melanocyte differentiation-associated protein (LRMDA).	[23]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11.Eur J Hum Genet. 2010 Mar;18(3):291-5. doi: 10.1038/ejhg.2009.163. Epub 2009 Oct 21.
• [3] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [4] De Novo 1.77-Mb Microdeletion of 10q22.2q22.3 in a Girl With Developmental Delay, Speech Delay, Congenital Cleft Palate, and Bilateral Hearing Impairment.Cleft Palate Craniofac J. 2017 May;54(3):343-350. doi: 10.1597/15-171. Epub 2016 Mar 31.
• [5] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [6] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [7] Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Am J Hum Genet. 2013 Mar 7;92(3):415-21. doi: 10.1016/j.ajhg.2013.01.006. Epub 2013 Feb 7.
• [8] A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.Hum Mol Genet. 2013 Oct 1;22(19):4021-9. doi: 10.1093/hmg/ddt248. Epub 2013 Jun 4.
• [9] A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.Hum Mol Genet. 2012 Apr 1;21(7):1665-72. doi: 10.1093/hmg/ddr597. Epub 2011 Dec 16.
• [10] A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1.Sci Rep. 2019 Jan 24;9(1):645. doi: 10.1038/s41598-018-37272-5.
• [11] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [12] GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.Nat Commun. 2017 Nov 17;8(1):1584. doi: 10.1038/s41467-017-01490-8.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] 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.
• [20] 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.
• [21] Use of transcriptomics in hazard identification and next generation risk assessment: A case study with clothianidin. Food Chem Toxicol. 2022 Aug;166:113212. doi: 10.1016/j.fct.2022.113212. Epub 2022 Jun 8.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] 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.
• [24] Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009 Dec 10;27(35):5972-8.