Inhibiting PMS1 ATPase activity reduces somatic CAG repeat expansion in Huntington’s disease iPSCs [Conference Abstract]

Binda, Caroline, Stone, Joseph, Menzies, Georgina ORCID: https://orcid.org/0000-0002-6600-6507, Wills, Christopher, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Allen, Nicholas ORCID: https://orcid.org/0000-0003-4009-186X and Massey, Thomas ORCID: https://orcid.org/0000-0002-9804-2131 2026. Inhibiting PMS1 ATPase activity reduces somatic CAG repeat expansion in Huntington’s disease iPSCs [Conference Abstract]. Journal of Neurology, Neurosurgery and Psychiatry 97 (Supp 2) , A30. 10.1136/jnnp-2026-ehdn.75

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Abstract

Background: Somatic expansion of the pathogenic CAG repeat region in the huntingtin gene has emerged as a key driver of Huntington’s disease (HD). DNA mismatch repair proteins identified through human genetic studies affect CAG repeat instability in iPSC and mouse models of HD. We have shown that homozygous PMS1 knockout prevented CAG repeat expansion in a patient-derived iPSC model of HD. Using whole exome sequencing of 683 individuals with HD with extremes of onset or phenotype relative to CAG length, we discovered damaging coding variants clustered in the putative ATPase domain of PMS1 that were associated predominantly with late-onset HD. Aim: To investigate the role of PMS1 ATPase activity in somatic expansion in HD-iPSCs. Methods/Techniques: We measured ATPase activity of recombinant wild-type, E27A (ATPase-dead), and N31A (ATP binding mutant) PMS1 proteins. Next, we complemented PMS1 knockout HD-iPSCs with inducible wild-type, E27A, or N31A PMS1. In parallel, we used CRIPSR-Cas9 to knock the E27A mutation into the endogenous PMS1 gene in HD-iPSCs. We then assessed protein expression and somatic expansion over 8 weeks in ­culture. Results: In complementation experiments, wild-type PMS1 was able to support somatic expansion. E27A and N31A PMS1 supported significantly less somatic expansion. Expansion rates correlated with PMS1 protein levels. Homozygous knock-in of E27A into PMS1 led to a significant 57% slowing of the expansion rate in HD-iPSCs. Conclusions: PMS1 ATP binding and hydrolysis stimulate somatic expansion in HD. PMS1 ATPase activity is an attractive therapeutic target in HD and other repeat-expansion disorders.

Item Type:	Short Communication
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	BMJ Publishing Group
ISSN:	0022-3050
Last Modified:	28 Oct 2026 12:31
URI:	https://orca.cardiff.ac.uk/id/eprint/190501

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