P.157 Dominant HSPB6 mutation in a myopathy patient

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HSPB6 (also known as Hsp20) is a small heat-shock protein (sHSP) showing highest expression is skeletal, cardiac and smooth muscles. In contrast to most sHSPs, HSPB6 does not readily assemble into large oligomers on its own. However, it heterodimerizes with HSPB1 and hetero-oligomerizes with HSPB1 and αB-crystallin (CRYAB, HSPB5), modulating their oligomer size and chaperone activity. HSPB6 may also be involved in BAG3-mediated autophagy. Mutations in several sHSPs lead to neuromuscular disease. While rare missense variants in <i>HSPB6</i> have been associated with cardiomyopathy, the gene has not been previously linked to skeletal muscle disease. We describe the likely pathogenic heterozygous <i>HSPB6</i> variant c.464delC (p.Pro155Argfs*25) in a 62-year-old man with onset of the disease at 43 years of age characterized by a proximal lower limb weakness and a respiratory insufficiency. At 60 years of age, he walks with 2 canes. Of note, he underwent a cataract surgery at 28 years of age. The single-nucleotide deletion causes a frameshift predicted to replace of the six C-terminal amino acid residues of the HSPB6 protein with 24 erroneous residues. Western blotting of patient biopsy showed the normal and extended HSPB6 proteins at a 50:50 ratio, indicating that the mutant protein is expressed and stable. Histological findings included infrequent central HSPB6 accumulation in the myofibers, and myotilin-positive cytoplasmic bodies. In cell culture experiments, mutant HSPB6 showed reduced solubility compared to the wild-type protein and affected the solubility of coexpressed wild-type HSPB6, HSPB1 and CRYAB. Immunofluorescence microscopy revealed altered CRYAB localization patterns in cells expressing mutant HSPB6. Our results suggest that the <i>HSPB6</i> c.464delC (p.Pro155Argfs*25) mutation may cause muscle disease through a gain-of-function mechanism interfering with the sHSP machinery.