Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.
BACKGROUND
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder and is characterized by significant clinical and genetic heterogeneity. Recently, mutations in both the small heat shock protein 27 (HSP27 or HSPB1) and 22 (HSP22 or HSPB8) genes have been reported to cause autosomal dominant CMT with minimal sensory involvement (CMT 2F/CMT2L) and autosomal dominant distal hereditary motor neuropathy type II (dHMN II).


METHODS
We analyzed the HSPB1 and HSPB8 genes in a large clinically well-characterized series of dHMN and CMT type 2 (CMT2) cases and families using linkage analysis and direct sequencing of these genes.


RESULTS
We identified a novel homozygous mutation in the alpha-crystallin domain of HSPB1 segregating in an autosomal recessive fashion in a family with distal HMN/CMT2. A further four heterozygous HSPB1 mutations were identified in four autosomal dominant families dHMN/CMT2, and two sporadic cases were identified with probable de novo mutations. In the autosomal dominant and autosomal recessive families, there were no clinical sensory findings, but reduced sural nerve action potential amplitudes were found in some affected individuals, indicating that long sensory axons are mildly affected in this predominantly motor disorder.


CONCLUSIONS
This extends the clinical and electrophysiologic spectrum of HSPB1 mutations and identifies four unreported dominant HSPB1 mutations and the first family where the HSPB1 mutation acts in a recessive way to cause distal HMN.
Houlden
H
H
Department of Molecular Neurosciences, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. h.houlden@ion.ucl.ac.uk
Laura
M
M
Wavrant-De Vrièze
F
F
Blake
J
J
Wood
N
N
Reilly
M M
MM
D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D010525:Peripheral Nerves / Q000503:physiopathology
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones