Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies.

Variants in HSPB8 are predominantly associated with peripheral neuropathies, but their occurrence in myopathies remains exceedingly rare. The genetic and clinical spectrum of HSPB8-related myopathy is not yet complete. Herein, we not only described the first Chinese case of HSPB8-related myopathy characterized by a novel heterozygous frameshift variant (c.576_579delinsCAG, p.Glu192Aspfs*55) in the C-terminal region of HSPB8, but also established the first association between this specific HSPB8 variant and pediatric-onset axial and limb-girdle myopathy. Muscle pathology revealed myofibrillar myopathy features and the novel pathological findings of inflammatory responses and vacuoles with sarcolemmal features pathology. Functional studies demonstrated significant colocalization of HSPB8 with autophagy markers and upregulation of autophagy-related proteins, which suggested that autophagic dysregulation may contribute to the pathological process of this disease. Furthermore, comprehensive bioinformatics analysis and molecular dynamics simulations revealed an increased propensity for aggregation, as well as altered structural and biochemical properties in the mutant HSPB8. Our study highlights the importance of considering HSPB8 mutations in early-onset axial and limb-girdle myopathy, expanding the genetic and phenotypic spectrum of the disease. Notably, our results underscore the critical role of autophagy dysregulation and aberrant protein aggregation in the pathogenesis, providing novel insights into potential therapeutic targets.