CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset.

CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset.

Publication date: Aug 08, 2019

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.”

gusella@helix.mgh.harvard.edu, Genetic Modifiers. of. Huntington’s. Disease. (GeM-HD). Consortium.. Electronic. address:. and Consortium, Genetic Modifiers. of. Huntington’s. Disease. (GeM-HD). CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset. 06622. 2019 Cell (178):4.

Concepts Keywords
CAA Human biology
Genetic Huntingtons
Glutamine Huntingtin
Huntingtin Trinucleotide repeat disorder
Huntington Branches of biology
Loci
Pathogenesis
Polymorphic
Somatic

Semantics

Type Source Name
pathway BSID DNA Repair
gene UNIPROT CISH
gene UNIPROT SLC6A4
gene UNIPROT HTT
disease MESH CAA
drug DRUGBANK L-Glutamine
gene UNIPROT NR4A2
gene UNIPROT ALG3

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