Genetics Research Seminar

Series Name Genetics
Speaker Prof Lesley Jones, Professor of Neurogenetics, Cardiff University
Type Lectures & Talks
When 26 Oct 2016, 02:00PM - 03:00PM
Venue Bennett Link Lower Ground Floor Lecture Theatre
Open To University staff and students
For Bookings Contact Lisa Boulton LMB24@LE.AC.UK
Abstract: Huntington’s disease (HD) is one of a number of disease caused by CAG triplet repeat expansions in the coding regions of genes. In HD, as in many of these diseases, longer repeat expansions are associated with earlier disease onset and anticipation, but not all the difference in age at onset is accounted for by CAG repeat length, implying the existence of additional modifying factors. We conducted a genome wide association study that detected genetic modifiers of age at onset in HD which implicated variation in genes of the DNA damage response/DNA repair pathways in altering HD age at onset. In order to investigate whether the mechanism underlying this involvement of the DNA damage response was HD specific or an effect at the level of the mutation type, the CAG expansion, we examined the multiple spinocerebellar ataxias (SCAs). These diseases are neurodegenerations all caused by CAG expansions in otherwise unrelated genes. We detected a significant association between the age of onset of disease and genetic variation in the same DNA damage response/repair pathways as in HD across these diseases. These data implicate a common genetic mechanism modulating age at onset in the CAG repeat diseases. Genetic defects in DNA repair underlie other neurodegenerative disorders such as ataxia-telangiectasia and recent work has demonstrated that double-stranded DNA breaks are critical in modulating early gene expression, which provides a potential mechanistic link between DNA-repair and neurodegeneration. DNA repair has also been demonstrated to be key in the somatic expansion of repeated sequences in mouse models of repeat disease, and somatic expansion of the expanded CAG tract in HTT is known to correlate with age at onset of HD. Genes that have a role in DNA integrity may underpin a common mechanism and provide new therapeutic targets across these diseases.

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