Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8H77DL)

• DOT Name: DNA-binding protein RFX6 (RFX6)
• Synonyms: Regulatory factor X 6; Regulatory factor X domain-containing protein 1
• Gene Name: RFX6
• Related Disease:
  Martinez-Frias syndrome
  Benign prostatic hyperplasia
  Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome
  Malabsorption syndrome
  Maturity-onset diabetes of the young
  Non-insulin dependent diabetes
  Obsolete Mitchell-Riley syndrome
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Neonatal diabetes mellitus
  Prostate carcinoma
  Melanoma
  Prostate cancer
  Prostate neoplasm
• UniProt ID: RFX6_HUMAN
• Pfam ID: PF02257
• Sequence:
  MAKVPELEDTFLQAQPAPQLSPGIQEDCCVQLLGKGLLVYPEETVYLAAEGQPGGEQGGG
  EKGEDPELPGAVKSEMHLNNGNFSSEEEDADNHDSKTKAADQYLSQKKTITQIVKDKKKQ
  TQLTLQWLEENYIVCEGVCLPRCILYAHYLDFCRKEKLEPACAATFGKTIRQKFPLLTTR
  RLGTRGHSKYHYYGIGIKESSAYYHSVYSGKGLTRFSGSKLKNEGGFTRKYSLSSKTGTL
  LPEFPSAQHLVYQGCISKDKVDTLIMMYKTHCQCILDNAINGNFEEIQHFLLHFWQGMPD
  HLLPLLENPVIIDIFCVCDSILYKVLTDVLIPATMQEMPESLLADIRNFAKNWEQWVVSS
  LENLPEALTDKKIPIVRRFVSSLKRQTSFLHLAQIARPALFDQHVVNSMVSDIERVDLNS
  IGSQALLTISGSTDTESGIYTEHDSITVFQELKDLLKKNATVEAFIEWLDTVVEQRVIKT
  SKQNGRSLKKRAQDFLLKWSFFGARVMHNLTLNNASSFGSFHLIRMLLDEYILLAMETQF
  NNDKEQELQNLLDKYMKNSDASKAAFTASPSSCFLANRNKGSMVSSDAVKNESHVETTYL
  PLPSSQPGGLGPALHQFPAGNTDNMPLTGQMELSQIAGHLMTPPISPAMASRGSVINQGP
  MAGRPPSVGPVLSAPSHCSTYPEPIYPTLPQANHDFYSTSSNYQTVFRAQPHSTSGLYPH
  HTEHGRCMAWTEQQLSRDFFSGSCAGSPYNSRPPSSYGPSLQAQDSHNMQFLNTGSFNFL
  SNTGAASCQGATLPPNSPNGYYGSNINYPESHRLGSMVNQHVSVISSIRSLPPYSDIHDP
  LNILDDSGRKQTSSFYTDTSSPVACRTPVLASSLQTPIPSSSSQCMYGTSNQYPAQETLD
  SHGTSSREMVSSLPPINTVFMGTAAGGT
• Function: Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin. Not required for pancreatic PP (polypeptide-producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes. Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription.
• Tissue Specificity: Expressed in pancreas . Expressed in pancreatic beta-cells (insulin-positive cells) and alpha-cells (glucagon-positive cells) (at protein level). Specifically expressed in pancreas, small intestine and colon . Expressed in endocrine cells in the islets .
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway: Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Martinez-Frias syndrome	DISRFDBA	Definitive	Autosomal recessive	[1]
Benign prostatic hyperplasia	DISI3CW2	Strong	Genetic Variation	[2]
Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome	DISDX9O0	Strong	Autosomal recessive	[3]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[4]
Maturity-onset diabetes of the young	DISG75M5	Strong	Genetic Variation	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[5]
Obsolete Mitchell-Riley syndrome	DISDKGR2	Strong	Autosomal recessive	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[5]
Neonatal diabetes mellitus	DISFHF9K	moderate	Genetic Variation	[8]
Prostate carcinoma	DISMJPLE	moderate	Genetic Variation	[9]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]
Prostate cancer	DISF190Y	Limited	Genetic Variation	[11]
Prostate neoplasm	DISHDKGQ	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DNA-binding protein RFX6 (RFX6).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA-binding protein RFX6 (RFX6).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-binding protein RFX6 (RFX6).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA-binding protein RFX6 (RFX6).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA-binding protein RFX6 (RFX6).	[16]

References

• [1] Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia. 2004 Dec;47(12):2160-7. doi: 10.1007/s00125-004-1576-3. Epub 2004 Dec 8.
• [2] Genetic variants in 2q31 and 5p15 are associated with aggressive benign prostatic hyperplasia in a Chinese population.Prostate. 2013 Aug;73(11):1182-90. doi: 10.1002/pros.22666. Epub 2013 Apr 26.
• [3] Rfx6 directs islet formation and insulin production in mice and humans. Nature. 2010 Feb 11;463(7282):775-80. doi: 10.1038/nature08748.
• [4] Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells whilerepressing genetic programs controllingserotonin production.Mol Metab. 2019 Nov;29:24-39. doi: 10.1016/j.molmet.2019.08.007. Epub 2019 Aug 13.
• [5] A heterozygous protein-truncating RFX6 variant in a family with childhood-onset, pregnancy-associated and adult-onset diabetes.Diabet Med. 2020 Oct;37(10):1772-1776. doi: 10.1111/dme.13970. Epub 2019 Jun 5.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Clinical characterization of a newly described neonatal diabetes syndrome caused by RFX6 mutations. Am J Med Genet A. 2011 Nov;155A(11):2821-5. doi: 10.1002/ajmg.a.34251. Epub 2011 Sep 30.
• [8] Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.Eur J Hum Genet. 2015 Dec;23(12):1744-8. doi: 10.1038/ejhg.2015.161. Epub 2015 Aug 12.
• [9] 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population.Nat Commun. 2019 Sep 27;10(1):4422. doi: 10.1038/s41467-019-12267-6.
• [10] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [11] Association of THADA, FOXP4, GPRC6A/RFX6 genes and 8q24 risk alleles with prostate cancer in Northern Chinese men.J BUON. 2015 Sep-Oct;20(5):1223-8.
• [12] A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.Nat Genet. 2014 Feb;46(2):126-35. doi: 10.1038/ng.2862. Epub 2014 Jan 5.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [16] 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.