Abstract
Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine–leucine–valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.
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Acknowledgements
This research was partially supported by Intramural Research Grants 29-4 for Neurological and Psychiatric Disorders provided to MA from the National Center of Neurology and Psychiatry of Japan; Grants-in-Aid for Research on Rare and Intractable Diseases (H29-nanchitou(nan)-ippan-030) provided to MA from the Ministry of Health, Labor and Welfare of Japan; a Grant-in-Aid for Challenging Exploratory Research (26670436) provided to MA, from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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Inoue-Shibui, A., Niihori, T., Kobayashi, M. et al. A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy. J Hum Genet 66, 965–972 (2021). https://doi.org/10.1038/s10038-021-00916-y
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DOI: https://doi.org/10.1038/s10038-021-00916-y
