A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.
Kristina BečanovićAnne NørremølleScott J NealChris KayJennifer A CollinsDavid ArenillasTobias LiljaGiulia GaudenziShiana ManoharanCrystal N DotyJessalyn BeckNayana LahiriElodie Portales-CasamarSimon C WarbyColúm ConnollyRebecca A G De Souzanull nullSarah J TabriziOla HermansonDouglas R LangbehnMichael R HaydenWyeth W WassermanBlair R LeavittPublished in: Nature neuroscience (2015)
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.
Keyphrases
- gene expression
- transcription factor
- dna methylation
- end stage renal disease
- genome wide
- signaling pathway
- ejection fraction
- newly diagnosed
- chronic kidney disease
- lps induced
- prognostic factors
- nuclear factor
- peritoneal dialysis
- inflammatory response
- wild type
- early onset
- binding protein
- high density
- toll like receptor
- heat stress
- heat shock