Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVX3J6S)

• DOT Name: LIM/homeobox protein Lhx4 (LHX4)
• Synonyms: LIM homeobox protein 4
• Gene Name: LHX4
• Related Disease:
  Short stature-pituitary and cerebellar defects-small sella turcica syndrome
  Acute lymphocytic leukaemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Childhood acute lymphoblastic leukemia
  Congenital myopathy
  Cyclic hematopoiesis
  Hypopituitarism
  Panhypopituitarism
  Pituitary dwarfism
  Pituitary hormone deficiency, combined, 1
  Acute myelogenous leukaemia
  Congenital isolated adrenocorticotropic hormone deficiency
  Combined pituitary hormone deficiencies, genetic form
  Hypothyroidism due to deficient transcription factors involved in pituitary development or function
  Pituitary stalk interruption syndrome
  Hypothyroidism
  Pituitary gland disorder
• UniProt ID: LHX4_HUMAN
• PDB ID: 5HOD
• Pfam ID: PF00046 ; PF00412
• Sequence:
  MMQSATVPAEGAVKGLPEMLGVPMQQIPQCAGCNQHILDKFILKVLDRHWHSSCLKCADC
  QMQLADRCFSRAGSVYCKEDFFKRFGTKCTACQQGIPPTQVVRKAQDFVYHLHCFACIIC
  NRQLATGDEFYLMEDGRLVCKEDYETAKQNDDSEAGAKRPRTTITAKQLETLKNAYKNSP
  KPARHVREQLSSETGLDMRVVQVWFQNRRAKEKRLKKDAGRHRWGQFYKSVKRSRGSSKQ
  EKESSAEDCGVSDSELSFREDQILSELGHTNRIYGNVGDVTGGQLMNGSFSMDGTGQSYQ
  DLRDGSPYGIPQSPSSISSLPSHAPLLNGLDYTVDSNLGIIAHAGQGVSQTLRAMAGGPT
  SDISTGSSVGYPDFPTSPGSWLDEMDHPPF
• Function: May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA.
• Reactome Pathway: Regulation of expression of SLITs and ROBOs (R-HSA-9010553)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Short stature-pituitary and cerebellar defects-small sella turcica syndrome	DIS11311	Definitive	Autosomal dominant	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[2]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[3]
Cyclic hematopoiesis	DISQQOM4	Strong	Genetic Variation	[4]
Hypopituitarism	DIS1QT3G	Strong	Genetic Variation	[5]
Panhypopituitarism	DISAKJ4T	Strong	Genetic Variation	[5]
Pituitary dwarfism	DISI019B	Strong	Genetic Variation	[5]
Pituitary hormone deficiency, combined, 1	DISVFM4T	Strong	GermlineCausalMutation	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Congenital isolated adrenocorticotropic hormone deficiency	DISYMJJV	moderate	Genetic Variation	[8]
Combined pituitary hormone deficiencies, genetic form	DISW6YL6	Supportive	Autosomal dominant	[6]
Hypothyroidism due to deficient transcription factors involved in pituitary development or function	DISCAAEX	Supportive	Autosomal dominant	[9]
Pituitary stalk interruption syndrome	DISGSN5T	Supportive	Autosomal dominant	[10]
Hypothyroidism	DISR0H6D	Limited	Genetic Variation	[11]
Pituitary gland disorder	DIS7XB48	Limited	Genetic Variation	[5]

2 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 protein Lhx4 (LHX4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of LIM/homeobox protein Lhx4 (LHX4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of LIM/homeobox protein Lhx4 (LHX4).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of LIM/homeobox protein Lhx4 (LHX4).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of LIM/homeobox protein Lhx4 (LHX4).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of LIM/homeobox protein Lhx4 (LHX4).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of LIM/homeobox protein Lhx4 (LHX4).	[16]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Aberrant expression of the LHX4 LIM-homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis.Genes Chromosomes Cancer. 2003 Nov;38(3):269-73. doi: 10.1002/gcc.10283.
• [3] LHX4 Gene Alterations: Patient Report and Review of the Literature.Pediatr Endocrinol Rev. 2016 Jun;13(4):749-55.
• [4] Gradual loss of ACTH due to a novel mutation in LHX4: comprehensive mutation screening in Japanese patients with congenital hypopituitarism.PLoS One. 2012;7(9):e46008. doi: 10.1371/journal.pone.0046008. Epub 2012 Sep 24.
• [5] Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients.J Clin Endocrinol Metab. 2017 Jan 1;102(1):290-301. doi: 10.1210/jc.2016-3158.
• [6] Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation. J Clin Endocrinol Metab. 2015 Jun;100(6):2158-64. doi: 10.1210/jc.2014-4484. Epub 2015 Apr 14.
• [7] 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.
• [8] Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue.PLoS One. 2015 May 8;10(5):e0126648. doi: 10.1371/journal.pone.0126648. eCollection 2015.
• [9] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [10] Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms. Eur J Endocrinol. 2011 Apr;164(4):457-65. doi: 10.1530/EJE-10-0892. Epub 2011 Jan 26.
• [11] DNA testing in patients with GH deficiency at the time of transition.Growth Horm IGF Res. 2003 Aug;13 Suppl A:S122-9. doi: 10.1016/s1096-6374(03)00068-6.
• [12] 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.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.