HIn a preprint posted on January 24, 2019 by Cold Spring Harbor Laboratory’s bioRxiv, the Genetic Modifiers of Huntington’s Disease Consortium (GeM-HD), including such prominent HD experts as James Gusella, PhD, and Marcy MacDonald, PhD, both of the Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital; and Jane Paulsen, PhD, Departments of Psychiatry and Neurology, University of Iowa, make the provocative suggestion that some property of the uninterrupted CAG repeat segment in exon 1 of the huntingtin-coding gene (HTT), distinct from the resulting too-lengthy polyglutamine segment of the huntingtin protein, determines the rate at which HD develops. The article is titled “Huntington's Disease Onset Is Determined by Length of Uninterrupted CAG, Not Encoded Polyglutamine, and Is Modified by DNA Maintenance Mechanisms” ((https://www.biorxiv.org/content/biorxiv/early/2019/01/24/529768.full.pdf). According to the article abstract, “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.
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