Molecular, cellular, and clinical aspects of myofibrillar myopathy caused by HSPB8 frameshift mutations

HSPB8 belongs to the small heat shock protein family, which comprises ten chaperones with molecular weights below 29 kDa. HSPB8 is broadly expressed across human tissues, with the highest levels in skeletal muscles, the cardiac muscle, and the nervous system. In muscles, HSPB8 plays a crucial role in chaperone-assisted selective autophagy (CASA), contributing to protein quality control and maintaining proteostasis. The most extensively studied mutations affecting the HSPB8 K141 codon are associated with autosomal dominant neuromuscular disorders such as Charcot-Marie-Tooth disease type 2L and distal hereditary motor neuropathy type 2 (dHMN2). Of note, recent findings have identified Myofibrillar Myopathy type 13 (MFM13) with Rimmed Vacuoles as a distinct disorder caused by frameshift (fs) mutations in the carboxy-terminus of HSPB8. This review focuses on the known HSPB8-fs mutations leading to MFM13, their associated clinical phenotypes and histological findings, and highlights the need to further understand the underlying etiologies and mechanisms.