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

Abstract

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.

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

“…Furthermore, these effects were specific to human HTT regulatory elements, since no such changes were observed in the endogenous mouse Htt mRNA (Figure 8B). We assayed other putative regulators of HTT , such as Creb (indirect evidence based on consensus binding site) and Nfkb1, for which there is direct evidence for regulation (Bečanović et al, 2015). Creb mRNA levels were unchanged (data not shown) but the striatal level of Nfkb1 mRNA, already reduced in the YAC128, was further slightly reduced by DR, possibly contributing to the downregulation of the transgene (Figure 8C).…”

“…The 3000 Kb of the 5′UT sequences for mouse Htt and human HTT share 91% homology, and consensus NF-κB binding sites are present in both. Interestingly, however, the recently characterized active NF-κB binding site diverges from mouse to human, although non-canonical NF-κB binding is prevalent (Bečanović et al, 2015; Wong et al, 2011). It is also possible that epigenetic changes evoked by DR contribute to a decrease in human HTT mRNA, as these can regulate Nfkb1 (Haiqun Jia et al, 2012).…”

Induced Pluripotent Stem Cells in Huntington’s Disease: Disease Modeling and the Potential for Cell-Based Therapy

“…Furthermore, patient-derived iPSCs harbor all disease-associated genetic components that render GABAergic neurons susceptible to the disease. Therefore, they represent the most genetically precise model and might be helpful to further investigate genetic factors related to HD pathogenesis [53, 54]. Moreover, gene-silencing technologies based on patient-specific iPSCs may offer a way to correct this monogenic disorder, paving the road for personalized medicine [44, 55, 56].…”

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

“…Second, there is also CAG-length independent phenotypic variation within a given polyQ disease (Figure 1B). Both these findings imply that factors beyond the polyQ stretch are co-determining disease onset (Ranum et al, 1994; DeStefano et al, 1996; Hayes et al, 2000; Wexler et al, 2004; van de Warrenburg et al, 2005; Kaltenbach et al, 2007; Branco et al, 2008; Lessing and Bonini, 2008; Bettencourt et al, 2011; Tezenas du Montcel et al, 2014; Bečanović et al, 2015). It was hypothesized that the differential effects of distinct polyQ proteins with polyQ tracts of similar lengths could be, at least in part, due to the sequences flanking the polyQ expansion (Nozaki et al, 2001).…”