Item request has been placed! ×
Item request cannot be made. ×
loading  Processing Request

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
اقرأ على الانترنت اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • Corporate Authors:
      REGISTRY Investigators of the European Huntington's Disease Network
    • المصدر:
      Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE
    • بيانات النشر:
      Publication: <2002->: New York, NY : Nature Publishing Group
      Original Publication: New York, NY : Nature America Inc., c1998-
    • الموضوع:
      Huntington Disease/*genetics ; Huntington Disease/*metabolism ; NF-kappa B/*metabolism ; Nerve Tissue Proteins/*genetics ; Polymorphism, Single Nucleotide/*genetics; Adult ; Age of Onset ; Alleles ; Cohort Studies ; DNA/genetics ; Gene Expression Regulation/physiology ; Genes, Reporter/genetics ; Humans ; Huntingtin Protein ; Huntington Disease/physiopathology ; Middle Aged ; Mutagenesis, Site-Directed ; Nerve Tissue Proteins/metabolism ; Protein Binding
    • نبذة مختصرة :
      Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.
    • References:
      Nat Rev Genet. 2015 Apr;16(4):197-212. (PMID: 25707927)
      Nature. 1998 Jan 22;391(6665):410-3. (PMID: 9450761)
      Genet Epidemiol. 2013 Feb;37(2):142-51. (PMID: 23184518)
      Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3872-6. (PMID: 9108071)
      Nucleic Acids Res. 2004 Jan 1;32(Database issue):D91-4. (PMID: 14681366)
      J Med Genet. 1995 May;32(5):399-400. (PMID: 7616551)
      Lancet Neurol. 2011 Jan;10 (1):83-98. (PMID: 21163446)
      Clin Genet. 2004 Apr;65(4):267-77. (PMID: 15025718)
      Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3498-503. (PMID: 14993615)
      Neurobiol Dis. 2006 Feb;21(2):444-55. (PMID: 16230019)
      Hum Mol Genet. 1996 Dec;5(12 ):1875-85. (PMID: 8968738)
      J Med Genet. 1997 May;34(5):371-4. (PMID: 9152833)
      Neuron. 1993 Nov;11(5):985-93. (PMID: 8240819)
      BMC Neurosci. 2006 Dec 05;7:80. (PMID: 17147801)
      Am J Hum Genet. 1997 May;60(5):1202-10. (PMID: 9150168)
      Nat Genet. 1993 Nov;5(3):259-65. (PMID: 8275091)
      Exp Neurol. 2001 Feb;167(2):215-26. (PMID: 11161610)
      J Mol Neurosci. 2012 Jun;47(2):311-21. (PMID: 22399227)
      Mol Neurodegener. 2009 Jan 08;4:3. (PMID: 19133136)
      Hum Mol Genet. 2005 May 15;14(10):1379-92. (PMID: 15829505)
      Nat Genet. 1993 Aug;4(4):398-403. (PMID: 8401589)
      Proc Natl Acad Sci U S A. 1996 Aug 20;93(17 ):9090-5. (PMID: 8799159)
      PLoS Comput Biol. 2008 Jan;4(1):e5. (PMID: 18208319)
      PLoS One. 2010 Mar 26;5(3):e9908. (PMID: 20361042)
      Nat Genet. 2009 Nov;41(11):1216-22. (PMID: 19838192)
      Trends Neurosci. 2005 Jan;28(1):37-43. (PMID: 15626495)
      Am J Hum Genet. 2001 Feb;68(2):313-24. (PMID: 11133364)
      Am J Med Genet A. 2004 Oct 1;130A(2):154-9. (PMID: 15372528)
      Oncogene. 2006 Jan 5;25(1):1-7. (PMID: 16278683)
      Trends Neurosci. 2001 Mar;24(3):182-8. (PMID: 11182459)
      Nat Rev Genet. 2001 Mar;2(3):165-74. (PMID: 11256068)
      Structure. 2002 Mar;10(3):383-91. (PMID: 12005436)
      Hum Mol Genet. 1994 Jan;3(1):65-7. (PMID: 8162053)
      Hum Genet. 2008 Nov;124(4):357-68. (PMID: 18784943)
      Hum Mol Genet. 2008 Apr 15;17(8):1137-46. (PMID: 18192679)
      Neurology. 1991 Jul;41(7):1117-23. (PMID: 1829794)
      Hum Mol Genet. 1998 May;7(5):791-800. (PMID: 9536082)
      J Neurochem. 2006 Feb;96(4):1121-9. (PMID: 16417581)
      J Clin Invest. 2011 Feb;121(2):500-7. (PMID: 21285523)
      Biochem J. 1998 Nov 15;336 ( Pt 1):227-34. (PMID: 9806905)
      Nat Rev Genet. 2011 Jun 01;12(7):465-74. (PMID: 21629274)
      Clin Genet. 2009 Mar;75(3):244-50. (PMID: 19250382)
      Hum Genet. 2010 Oct;128(4):453-9. (PMID: 20697744)
      Science. 2010 Apr 9;328(5975):232-5. (PMID: 20299548)
      Neurosci Lett. 2002 Aug 2;328(1):1-4. (PMID: 12123845)
      Nat Genet. 2012 Jul 08;44(8):886-9. (PMID: 22772370)
      J Huntingtons Dis. 2013;2(4):491-500. (PMID: 25062733)
    • Grant Information:
      MR/L012936/1 United Kingdom MRC_ Medical Research Council; MR/L02053X/1 United Kingdom MRC_ Medical Research Council
    • الرقم المعرف:
      0 (HTT protein, human)
      0 (Huntingtin Protein)
      0 (NF-kappa B)
      0 (Nerve Tissue Proteins)
      9007-49-2 (DNA)
    • الموضوع:
      Date Created: 20150505 Date Completed: 20150806 Latest Revision: 20240306
    • الموضوع:
      20240306
    • الرقم المعرف:
      10.1038/nn.4014
    • الرقم المعرف:
      25938884