Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond somatic instability
Year: 2026
Type: preprint
Abstract: Huntington disease is a fatal neurodegenerative disorder caused by CAG repeat expansion encoding polyglutamine in the HTT gene. Recent studies have shown that loss of CAA/CCA interruptions within polyglutamine-coding CAG tracts and adjacent polyproline-coding region are linked to earlier disease onset. It has been hypothesized that somatic repeat instability, influenced by these interrupted CAG tracts, may mediate this effect. Here we demonstrate that HTT CAA/CCA-loss variant linked to early disease onset exacerbates mutant HTT toxicity in cellular models through mechanisms independent of somatic repeat instability. The CAA/CCA-loss variant exhibits significantly higher toxicity than canonical HTT sequences in both transient expression and stable cell line models. Notably, this enhanced toxicity persists in knockout cells of the mismatch repair gene MSH3 where somatic instability is blunted, with a consistent toxicity hierarchy (CAA/CCA-loss > CCA-loss > CAA-loss > canonical HTT) in both wildtype and MSH3 knockout cells. Furthermore, the CAA/CCA-loss variant generates elevated levels of repeat-associated non-AUG (RAN) translation products. In HEK293-based cellular models, these results suggest that the disease-accelerating effects of HTT CAA/CCA-loss variants involve intrinsic properties of the altered sequence context, highlighting the importance of understanding sequence-specific mechanisms in HD pathogenesis beyond polyglutamine length and somatic instability.
Authors: Glen L. Sequiera, Sophia C. Gjervan, Ryan McCallum, Jia Feng, Oguz K. Ozgoren, Sofia Bergh, Jocelyn Bégin, Jessica Levesley, Hailey Findlay Black, Chris Kay, Tanushri Soomarooah, Larissa Arning, Indhu Shree Rajan Babu, A. Nazlı Başak, Jiří Klempíř, Huu Phuc Nguyen, Åsa Petersen, Michael R. Hayden, Mahmoud A. Pouladi
Institutions: University of British Columbia, BC Children's Hospital Research Institute, Djavad Mowafaghian Centre for Brain Health, Lund University, University of Auckland, Ruhr University Bochum, Children's & Women's Health Centre of British Columbia, Koç University, Suna and İnan Kıraç Foundation, Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi, Charles University, General University Hospital in Prague, Skåne University Hospital
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Children's Health Research Institute, BC Children's Hospital, EU Joint Programme – Neurodegenerative Disease Research, Michael Smith Health Research BC, Bundesministerium für Bildung und Forschung, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, Koç Üniversitesi, Canadian Institutes of Health Research
OpenAlex ID: W7211927696