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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-alpha-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 publication

DOI

10.1038/ng1354

Type

Journal article

Journal

Nat Genet

Publication Date

06/2004

Volume

36

Pages

602 - 606

Keywords

Amino Acid Sequence, Animals, Base Sequence, Cell Line, Charcot-Marie-Tooth Disease, DNA, Complementary, Female, HSP27 Heat-Shock Proteins, Heat-Shock Proteins, Hereditary Sensory and Motor Neuropathy, Humans, Male, Mice, Molecular Sequence Data, Mutation, Missense, Neoplasm Proteins, Nerve Degeneration, Recombinant Proteins, Sequence Homology, Amino Acid, Transfection