Cell
Volume 178, Issue 4, 8 August 2019, Pages 887-900.e14
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Article
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset

https://doi.org/10.1016/j.cell.2019.06.036Get rights and content
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Highlights

  • Uninterrupted CAG repeat, not polyglutamine, size drives the timing of HD onset

  • HD age at onset is influenced by at least six genes involved in DNA maintenance

  • Genetic modifier loci often show both onset-delaying and onset-hastening haplotypes

  • The rate-determining mechanism is likely to be somatic expansion of the CAG repeat

Summary

Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin’s polyglutamine segment, dictates the rate at which Huntington’s disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the “polyglutamine disorders.”

Keywords

Huntington’s disease
CAG repeat
trinucleotide repeat
genetic modifier
age at onset
somatic DNA expansion
DNA maintenance
DNA repair
polyglutamine disease
disease modification

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Lead contact (James F. Gusella)