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- Title
Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.
- Authors
McLean, Zachariah L.; Gao, Dadi; Correia, Kevin; Roy, Jennie C. L.; Shibata, Shota; Farnum, Iris N.; Valdepenas-Mellor, Zoe; Kovalenko, Marina; Rapuru, Manasa; Morini, Elisabetta; Ruliera, Jayla; Gillis, Tammy; Lucente, Diane; Kleinstiver, Benjamin P.; Lee, Jong-Min; MacDonald, Marcy E.; Wheeler, Vanessa C.; Mouro Pinto, Ricardo; Gusella, James F.
- Abstract
Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites. Somatic expansion of a CAG repeat in HTT drives onset of Huntington's disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-47485-0