Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM8145D)

• DOT Name: LIM homeobox transcription factor 1-beta (LMX1B)
• Synonyms: LIM/homeobox protein 1.2; LMX-1.2; LIM/homeobox protein LMX1B
• Gene Name: LMX1B
• Related Disease:
  Chronic renal failure
  End-stage renal disease
  Familial Mediterranean fever
  Nail-patella syndrome
  Vesicoureteral reflux
  Attention deficit hyperactivity disorder
  Autism
  Breast carcinoma
  Carcinoma of esophagus
  Craniosynostosis
  Esophageal cancer
  Focal segmental glomerulosclerosis
  Genitopatellar syndrome
  Glomerulosclerosis
  Gray platelet syndrome
  Kidney failure
  Major depressive disorder
  Neoplasm of esophagus
  Open-angle glaucoma
  OPTN-related open angle glaucoma
  Parkinson disease
  Renal dysplasia
  Trichohepatoenteric syndrome
  Acute myelogenous leukaemia
  Advanced cancer
  Clubfoot
  Glaucoma/ocular hypertension
  Nail-patella-like renal disease
  Epithelial ovarian cancer
  Hyperlipidemia
  Insomnia
  Mental disorder
  Neoplasm
  Neurodevelopmental disorder
  Ovarian cancer
  Ovarian neoplasm
  Schizophrenia
  Sleep disorder, initiating and maintaining sleep
• UniProt ID: LMX1B_HUMAN
• Pfam ID: PF00046 ; PF00412
• Sequence:
  MDIATGPESLERCFPRGQTDCAKMLDGIKMEEHALRPGPATLGVLLGSDCPHPAVCEGCQ
  RPISDRFLMRVNESSWHEECLQCAACQQALTTSCYFRDRKLYCKQDYQQLFAAKCSGCME
  KIAPTEFVMRALECVYHLGCFCCCVCERQLRKGDEFVLKEGQLLCKGDYEKEKDLLSSVS
  PDESDSVKSEDEDGDMKPAKGQGSQSKGSGDDGKDPRRPKRPRTILTTQQRRAFKASFEV
  SSKPCRKVRETLAAETGLSVRVVQVWFQNQRAKMKKLARRHQQQQEQQNSQRLGQEVLSS
  RMEGMMASYTPLAPPQQQIVAMEQSPYGSSDPFQQGLTPPQMPGDHMNPYGNDSIFHDID
  SDTSLTSLSDCFLGSSDVGSLQARVGNPIDRLYSMQSSYFAS
• Function: Transcription factor involved in the regulation of podocyte-expressed genes. Essential for the specification of dorsal limb fate at both the zeugopodal and autopodal levels.
• Tissue Specificity: Expressed in most tissues. Highest levels in testis, thyroid, duodenum, skeletal muscle, and pancreatic islets.

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
End-stage renal disease	DISXA7GG	Definitive	Genetic Variation	[1]
Familial Mediterranean fever	DISVP5WP	Definitive	Genetic Variation	[2]
Nail-patella syndrome	DIS8C4CT	Definitive	Autosomal dominant	[3]
Vesicoureteral reflux	DISUL6SA	Definitive	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[7]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[8]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[7]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[9]
Genitopatellar syndrome	DIS5E2L7	Strong	Biomarker	[10]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[11]
Gray platelet syndrome	DISLOTCW	Strong	Biomarker	[10]
Kidney failure	DISOVQ9P	Strong	Biomarker	[12]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[7]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[13]
OPTN-related open angle glaucoma	DISDR98A	Strong	Biomarker	[14]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[15]
Renal dysplasia	DIS3DFGD	Strong	Genetic Variation	[16]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[17]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[18]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[19]
Clubfoot	DISLXT4S	moderate	Biomarker	[20]
Glaucoma/ocular hypertension	DISLBXBY	moderate	Genetic Variation	[13]
Nail-patella-like renal disease	DIS3M7W6	Supportive	Autosomal dominant	[21]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[22]
Hyperlipidemia	DIS61J3S	Limited	Biomarker	[23]
Insomnia	DIS0AFR7	Limited	Biomarker	[23]
Mental disorder	DIS3J5R8	Limited	Biomarker	[23]
Neoplasm	DISZKGEW	Limited	Altered Expression	[22]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[23]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[22]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[22]
Schizophrenia	DISSRV2N	Limited	Altered Expression	[24]
Sleep disorder, initiating and maintaining sleep	DISVOIRA	Limited	Biomarker	[23]

3 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 LIM homeobox transcription factor 1-beta (LMX1B).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of LIM homeobox transcription factor 1-beta (LMX1B).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of LIM homeobox transcription factor 1-beta (LMX1B).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of LIM homeobox transcription factor 1-beta (LMX1B).	[26]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of LIM homeobox transcription factor 1-beta (LMX1B).	[27]
Morphine	DMRMS0L	Approved	Morphine increases the expression of LIM homeobox transcription factor 1-beta (LMX1B).	[28]

References

• [1] Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms?.Eur J Hum Genet. 2018 Nov;26(11):1708-1712. doi: 10.1038/s41431-018-0213-4. Epub 2018 Jul 4.
• [2] Co-occurrence of familial Mediterranean fever (FMF) heterozygote mutation and nail-patella syndrome (NPS) in 3 members of a family with LMX1B mutation analysis.Genet Couns. 2007;18(2):259-62.
• [3] 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.
• [4] Increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in Nail-patella syndrome: potential association with LMX1B loss-of-function.Am J Med Genet B Neuropsychiatr Genet. 2011 Jan;156B(1):59-66. doi: 10.1002/ajmg.b.31138. Epub 2010 Nov 2.
• [5] Association of transcription factor gene LMX1B with autism.PLoS One. 2011;6(8):e23738. doi: 10.1371/journal.pone.0023738. Epub 2011 Aug 25.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] LMX1B involved in the radioresistance, proliferation and migration of esophageal cancer cells.Biomed Pharmacother. 2019 Oct;118:109358. doi: 10.1016/j.biopha.2019.109358. Epub 2019 Aug 29.
• [8] Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria.Dev Biol. 2018 Nov 15;443(2):103-116. doi: 10.1016/j.ydbio.2018.05.022. Epub 2018 May 28.
• [9] Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.Sci Rep. 2017 Jan 6;7:39933. doi: 10.1038/srep39933.
• [10] Ovotestes and XY sex reversal in a female with an interstitial 9q33.3-q34.1 deletion encompassing NR5A1 and LMX1B causing features of Genitopatellar syndrome.Am J Med Genet A. 2007 May 15;143A(10):1071-81. doi: 10.1002/ajmg.a.31685.
• [11] Renal phenotype in heterozygous Lmx1b knockout mice (Lmx1b+/-) after unilateral nephrectomy.Transgenic Res. 2007 Dec;16(6):723-9. doi: 10.1007/s11248-007-9118-7. Epub 2007 Jul 27.
• [12] LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy.Nephrol Dial Transplant. 2014 Jan;29(1):81-8. doi: 10.1093/ndt/gft359. Epub 2013 Sep 15.
• [13] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [14] SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma.Mol Vis. 2012;18:1629-39. Epub 2012 Jun 19.
• [15] Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4387-96. doi: 10.1073/pnas.1520387113. Epub 2016 Jul 12.
• [16] Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.Nat Genet. 1998 May;19(1):47-50. doi: 10.1038/ng0598-47.
• [17] Novel LMX1B mutation in familial nail-patella syndrome with variable expression of open angle glaucoma.Mol Vis. 2007 Apr 27;13:639-48.
• [18] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [19] LMX1B mRNA expression and its gene body CpG methylation are valuable prognostic biomarkers for laryngeal squamous cell carcinoma.Biomed Pharmacother. 2019 Sep;117:109174. doi: 10.1016/j.biopha.2019.109174. Epub 2019 Jul 8.
• [20] Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment.Nephrol Dial Transplant. 2009 Apr;24(4):1335-8. doi: 10.1093/ndt/gfn725. Epub 2009 Jan 15.
• [21] A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'. Clin Kidney J. 2015 Feb;8(1):113-9. doi: 10.1093/ckj/sfu129. Epub 2014 Dec 5.
• [22] Identification of LMX1B as a novel oncogene in human ovarian cancer.Oncogene. 2014 Aug 14;33(33):4226-35. doi: 10.1038/onc.2013.375. Epub 2013 Sep 23.
• [23] Nail-patella syndrome with an emphasis on the risk of renal and ocular findings.Pediatr Dermatol. 2010 Jan-Feb;27(1):95-7. doi: 10.1111/j.1525-1470.2009.01051.x.
• [24] Schizophrenia and Nail Patella Syndrome: The Dopamine Connection.Isr Med Assoc J. 2018 Aug;20(8):496-498.
• [25] 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.
• [26] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [27] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [28] Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim Biophys Acta. 2009 Aug;1790(8):793-9. doi: 10.1016/j.bbagen.2009.04.011. Epub 2009 May 3.
• [29] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [30] 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.