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Lookup NU author(s): Dr Goknur Kocak, Dr Ana TopfORCiD, Professor Chiara Marini Bettolo, Dr Lizzie Harris, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Heat shock protein family B (small) member 8 (HSPB8) promotes chaperone-assisted selective autophagy (CASA), which assures proteostasis in muscles and neurons. HSPB8 frameshift mutations found in neuromyopathies are translated on the same frame, generating the same C-terminal extension, which causes HSPB8 aggregation and proteostasis defects. Here, we describe three novel HSPB8 frameshift variants, translated to protein using the third alternative frame to stop codons downstream to the canonical one and to the one used by other known HSPB8 frameshift mutants. Therefore, these variants are predicted to encode a C-terminal extension that is different in length and amino acids. HSPB8 c.562delC and c.520_523delTACT were identified in two unrelated sporadic patients, while c.515delC, in a familial case of early-onset myopathy. Patients may differentially exhibit additional pathological features, such as neuropathy, respiratory insufficiency, and, remarkably, severe cardiomyopathy. Skeletal muscle biopsies revealed variations in fiber size, atrophy, multiple vacuoles, fat infiltration, and eosinophilic inclusions. In a reconstituted cell model of disease the expression of one representative novel HSPB8 mutant results in i) aggregation of the HSPB8 mutant, ii) sequestration of both the HSPB8 wild-type and CASA complex members, as well as iii) the autophagy receptor sequestosome-1 (SQSTM1/p62), iv) accumulation of ubiquitinated substrates, and v) defects in CASA-mediated degradation. Our results prove that the last exon of the HSPB8 gene is highly susceptible to pathogenic mutations, resulting in a wider phenotypic spectrum associated with HSPB8 frameshift variants. Our studies suggest the importance of HSPB8 genetic testing not only for neuropathy and myopathy but also for cardiomyopathy.
Author(s): Tedesco B, Peric S, Kocak GS, Tan J, Duong H, Topf A, Rakocevic-Stojanovic V, Milenkovic S, Parkhurst Y, Gibbs L, Martin-Rios A, Lambiase PD, Guttmann OP, Marini-Bettolo C, Harris E, Harms MB, Ivanovic V, Marchesi V, Milone M, Timmerman V, Straub V, Poletti A, Kimonis V
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2025
Pages: epub ahead of print
Online publication date: 04/06/2025
Acceptance date: 06/05/2025
Date deposited: 16/06/2025
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41431-025-01868-z
DOI: 10.1038/s41431-025-01868-z
Data Access Statement: The data that support the findings of this study are available from the corresponding author, upon reasonable request
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