Type 2F Mutation research

[Guest guest]

Research From Nat Genet. 2004 May 2 Epub 2004 May 02.

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth

disease and distal hereditary motor neuropathy.

Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung

CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E,

Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton- D,

Talbot K, JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK,

Gettemans J, Robberecht W, De Jonghe P, Timmerman V.

Department of Psychiatry, New York State Psychiatric Institute/Research

Foundation for Mental Hygiene, Unit 28, 1051 Riverside Drive, New York,

New York 10032, USA.

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.