Jordan Green
Research Mentor: Catherine Kaczorowski
Mentor Department: Neurology, Medicine
Author(s): Jordan Green, Augustine Vanlianuk, Stephanie Boas, Catherine Kaczorowski
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 104
Abstract
Huntington’s Disease (HD) is an autosomal dominantly inherited trait, caused by an increased CAG repeat length in the HTT gene of chromosome four. Onset of motor and cognitive symptoms are predicted by the length of CAG repeats. The few genetic variants predicted to modify (HD) onset identified through Genome Wide Association Studies (GWAS) are largely associated with DNA mismatch repair. These variants are largely predicted to affect HD progression by altering the rate/stability of somatic mHTT CAG expansion, which correlates to HD severity. TCERG1, a gene that is predicted to harbor protective variants, is a notable exception; the mechanism by which TCERG1 variants are protective in HD are completely unknown, though animal knockout and overexpression studies predict that this modifier does not affect somatic stability. We are investigating TCERG1 mechanisms using a novel CRISPR-modified mouse population that recapitulates a GWAS-identified HD-modifying variant. We are utilizing qPCR to assess if the CRISPR modification alters Tcerg1 expression in relevant brain regions of HD transgenic mice and non-transgenic littermates. These mice were tested on cognitive performance tasks, so we are also investigating if Tcerg1 levels predict cognitive performance in HD and/or in littermate controls. Lastly, we are investigating if the Tcerg1 CRISPR modification affects germline inheritance patterns of mHtt CAG length transmitted to offspring. This analysis will inform if the germline inheritance and somatic instability mechanisms are independent of one another, and how the presence of the CRISPR-modified Tcerg1 variant affects those mechanisms.
