Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy

Oleg V. Evgrafov, Irena Mersiyanova, Joy Irobi, Ludo V. Van Den Bosch, Ines Dierick, Conrad L. Leung, Olga Schagina, Nathalie Verpoorten, Katrien Van Impe, Valeriy Fedotov, Elena Dadali, Michaela Auer-Grumbach, Christian Windpassinger, Klaus Wagner, Zoran Mitrovic, David Hilton-Jones, Kevin Talbot, Jean Jacques Martin, Natalia Vasserman, Svetlana TverskayaAlexander Polyakov, Ronald K.H. Liem, Jan Gettemans, Wim Robberecht, Peter De Jonghe, Vincent Timmerman

Research output: Contribution to journalArticlepeer-review

527 Scopus citations


Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. 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.

Original languageEnglish (US)
Pages (from-to)602-606
Number of pages5
JournalNature genetics
Issue number6
StatePublished - Jun 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics


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