EP 7: Tedesco et al. 2025: How New Frameshifts Change HSPB8 Disease

In this episode, we look at the 2025 study by Tedesco et al., “Novel HSPB8 mutations in severe early-onset myopathy with involvement of respiratory and cardiac muscles cause proteostasis defects in cell models,” published in the European Journal of Human Genetics. The researchers revealed three new mutations in HSPB8 that result in a previously undescribed frameshift. These mutations create a longer C-terminal end of the protein with a different amino acid sequence than those described before. This structural change is linked to an even more severe disease picture: earlier muscle weakness, sometimes combined with reduced involvement, breathing difficulties, and even cardiac problems. The study not only presents detailed case reports but also builds on Tedesco et al., 2023 (Episode 5), which showed how elongated C-terminal mutations disrupt the cell’s clean-up system. In the 2025 work, scientists demonstrate that these new frameshifts also cause toxic aggregation of CASA complex proteins, further impairing the cell’s ability to remove damaged proteins. These results highlight the vulnerability of the HSPB8 gene’s last exon and broaden both the molecular and clinical understanding of HSPB8-related myopathies and neuromyopathies