Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond…

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.

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BibTeX RIS

BibTeX

@misc{sequiera2026synonymous,
  title = {{Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond somatic instability}},
  author = {G. L. Sequiera and S. C. Gjervan and R. McCallum and J. Feng and O. K. Ozgoren and S. Bergh and J. Begin and J. Levesley and H. Findlay Black and C. Kay and T. Soomarooah and L. Arning and I. S. Rajan Babu and A. N. Basak and J. Klempir and H. P. Nguyen and A. Petersen and M. R. Hayden and M. A. Pouladi},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.03.749261},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749261v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond somatic instability
AU  - G. L. Sequiera
AU  - S. C. Gjervan
AU  - R. McCallum
AU  - J. Feng
AU  - O. K. Ozgoren
AU  - S. Bergh
AU  - J. Begin
AU  - J. Levesley
AU  - H. Findlay Black
AU  - C. Kay
AU  - T. Soomarooah
AU  - L. Arning
AU  - I. S. Rajan Babu
AU  - A. N. Basak
AU  - J. Klempir
AU  - H. P. Nguyen
AU  - A. Petersen
AU  - M. R. Hayden
AU  - M. A. Pouladi
PY  - 2026
DA  - 2026/09/03
PB  - bioRxiv
DO  - 10.64898/2026.09.03.749261
UR  - https://www.biorxiv.org/content/10.64898/2026.09.03.749261v1
AB  - 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.
ER  -

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