title: Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.
abstract: 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.
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Unit 28, 1051 Riverside Drive, New York, New York 10032, USA. Evgrafo@pi.cpmc.columbia.edu
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgrafov
authors.forename: Irena
authors.initials: I
authors.lastname: Mersiyanova
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Ines
authors.initials: I
authors.lastname: Dierick
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Leung
authors.forename: Olga
authors.initials: O
authors.lastname: Schagina
authors.forename: Nathalie
authors.initials: N
authors.lastname: Verpoorten
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Impe
authors.forename: Valeriy
authors.initials: V
authors.lastname: Fedotov
authors.forename: Elena
authors.initials: E
authors.lastname: Dadali
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.forename: Klaus
authors.initials: K
authors.lastname: Wagner
authors.forename: Zoran
authors.initials: Z
authors.lastname: Mitrovic
authors.forename: David
authors.initials: D
authors.lastname: Hilton-Jones
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Natalia
authors.initials: N
authors.lastname: Vasserman
authors.forename: Svetlana
authors.initials: S
authors.lastname: Tverskaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Polyakov
authors.forename: Ronald K H
authors.initials: RK
authors.lastname: Liem
authors.forename: Jan
authors.initials: J
authors.lastname: Gettemans
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011994:Recombinant Proteins