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

Huntington disease is a fatal neurodegenerative disorder caused by an expansion of CAG repeats in the HTT gene. Recent research has suggested that loss of CAA/CCA interruptions within these CAG tracts and a nearby polyproline-coding region can lead to earlier onset of the disease. Scientists hypothesized that somatic repeat instability, which is influenced by these interrupted CAG tracts, might be responsible for this effect.

However, a new study demonstrates that variants of the HTT gene with CAA/CCA losses, which are associated with early disease onset, enhance mutant HTT toxicity in cellular models through mechanisms that are not related to somatic instability.

The HTT CAA/CCA-loss variant shows significantly greater toxicity compared to normal HTT sequences in both temporary expression and stable cell line experiments. This increased toxicity continues to be observed even when mismatch repair gene MSH3 is removed, a gene typically associated with somatic instability. The results indicate a consistent toxicity hierarchy (CAA/CCA-loss > CCA-loss > CAA-loss > canonical HTT) in both normal and MSH3 knockout cells.

Additionally, the CAA/CCA-loss variant produces higher amounts of repeat-associated non-AUG (RAN) translation products. In cellular models using HEK293 cells, these findings suggest that the disease-accelerating effects of HTT CAA/CCA-loss variants are due to intrinsic properties of the altered sequence context. This highlights the significance of understanding sequence-specific mechanisms in the development of Huntington's disease, beyond just the length of the polyglutamine stretch and somatic instability.