Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Through international collaboration with research groups in Australia and USA the Udd Group discovered a novel disease and pathology due to mutations in the small heat shock protein 22 gene (HSPB8 also called HSP22) located on chromosome 2 12q24.23. The two families studied had an autosomal dominant distal neuromuscular disease. Affected members of the families had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component, both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy.

The Udd Group performed whole-exome sequencing (WES) on two samples from affected members of family 1. This was done in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) on the proband from family 2, using version 2 of our MYOcap gene panel. The panel is targeted to the exons of 236 genes that are known or predicted to cause muscular dystrophy or myopathy. By these approaches the Udd Group identified heterozygous changes in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. The two detected variants and their familial segregation with the disease were confirmed using Sanger sequencing. By functional studies through transient co-transfection of an aggregation prone protein (GFP-120Q-HTT) and HSPB8 constructs, a loss of ability to prevent aggregation was observed for the mutant HSPB8 protein.

With this study the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations has been expanded. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, it has been now demonstrated that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles. These are similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects.

Original study:

Ghaoui R, Palmio J, Brewer J, Lek M, Needham M, Evilä A, Hackman P, Jonson PH, Penttilä S, Vihola A, Huovinen S, Lindfors M, Davis RL, Waddell L, Kaur S, Yiannikas C, North K, Clarke N, MacArthur DG, Sue CM, Udd B. Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology 86: 391-398, 2016