Abstract
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity1. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11–q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20–α-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.
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Acknowledgements
We thank the affected individuals and their relatives for participating in this research project; A. Jacobs, E. De Vriendt, V. Van Gerwen, D. Kiraly and M. Jug for technical assistance; and A. Stavljenic-Rukavina for referring one of the families and for institutional support to Z.M.. This research project was supported in part by the Association Française contre les Myopathies, the Association Belge contre les Maladies Neuromusculaires, the Muscular Dystrophy Association, the US National Institutes of Health, Columbia University, the Concerted Research Actions of the Universities of Ghent, Leuven and Antwerp, the Fund for Scientific Research-Flanders, the Medical Foundation Queen Elisabeth, the Belgian Federal Science Policy Office, the Austrian Science Fund and the Styrian government. I.D. and N.V. are PhD students supported by the Institute for Science and Technology, Belgium.
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Evgrafov, O., Mersiyanova, I., Irobi, J. et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36, 602–606 (2004). https://doi.org/10.1038/ng1354
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DOI: https://doi.org/10.1038/ng1354
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