Journal article
CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset
Cell, Vol.178(4), pp.887-900.e14
08/08/2019
DOI: 10.1016/j.cell.2019.06.036
PMCID: PMC6700281
PMID: 31398342
Abstract
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.”
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•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
The onset of Huntington’s disease is shown to be dependent on the size of the uninterrupted CAG repeat sequence, not polyglutamine.
Details
- Title: Subtitle
- CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset
- Creators
- Jong-Min LeeKevin CorreiaJacob LoupeKyung-Hee KimDouglas BarkerEun Pyo HongMichael J ChaoJeffrey D LongDiane LucenteJean Paul G VonsattelRicardo Mouro PintoKawther Abu ElneelEliana Marisa RamosJayalakshmi Srinidhi MysoreTammy GillisVanessa C WheelerMarcy E MacDonaldJames F GusellaBranduff McAllisterThomas MasseyChristopher MedwayTimothy C StoneLynsey HallLesley JonesPeter HolmansSeung KwakAnka G EhrhardtCristina SampaioMarc CiosiAlastair MaxwellAfroditi ChatziDarren G MoncktonMichael OrthG. Bernhard LandwehrmeyerJane S PaulsenE. Ray DorseyIra ShoulsonRichard H MyersGenetic Modifiers of Huntington’s Disease (GeM-HD) Consortium
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.178(4), pp.887-900.e14
- DOI
- 10.1016/j.cell.2019.06.036
- PMID
- 31398342
- PMCID
- PMC6700281
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100005725, name: CHDI Foundation; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/501100000265, name: Medical Research Council
- Language
- English
- Date published
- 08/08/2019
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984280872002771
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