C-terminal extension of HSPB6 in a family with myopathy and cataract

The small heat shock protein HSPB6 (a.k.a. Hsp20) is highly expressed in striated and smooth muscles. It modulates the oligomerization of its paralogs HSPB1 and CRYAB (HSPB5) and is involved e.g. in cytoskeletal regulation and autophagy. While HSPB6 variants have been implicated in cardiomyopathy, they have not been previously linked to neuromuscular disease. We report here a patient with late-onset myopathy and cataract, carrying in cis the novel HSPB6 variant c.464delC and the common polymorphism c.488G > C, together resulting in the extended protein p.Pro155Argfs*25;p.Gly163Arg. The family history was consistent with dominant inheritance. The mutant protein showed decreased solubility due to phase separation propensity, and caused mislocalization of CRYAB and BAG3, and a decrease of HSPB1 in transfected cells. The patient's muscle biopsy showed rimmed vacuoles and, in line with the functional studies, accumulation of HSPB6 and its interaction partners. The identified HSPB6 variants are most likely the cause of the muscle disease in this family, thus identifying HSPB6 mutations as a novel cause of vacuolar myopathy. Other reported HSPB6 variants causing a late frameshift or extension may cause disease in a similar fashion.