Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach.
OBJECTIVE
Idiopathic peripheral neuropathy is common and likely due to genetic factors that are not detectable using standard linkage analysis. We initiated a candidate gene approach to study the genetic influence of the small heat shock protein (sHSP) gene family on an axonal motor and motor/sensory neuropathy patient population.


METHODS
The promoter region and all exonic and intronic sequences of the 10 sHSP genes (HSPB1-HSPB10) were screened in a cohort of presumed nonacquired, axonal motor and motor/sensory neuropathy patients seen at the Ohio State University Neuromuscular Clinic.


RESULTS
A missense mutation in the gene encoding small heat shock protein B3 (HSPB3, also called HSP27, protein 3) was discovered in 2 siblings with an asymmetric axonal motor neuropathy. Electrophysiologic studies revealed an axonal, predominantly motor, length-dependent neuropathy. The mutation, HSPB3(R7S), is located in the N-terminal domain and involves the loss of a conserved arginine.


CONCLUSIONS
The discovery of an HSPB3 mutation associated with an axonal motor neuropathy using a candidate gene approach supports the notion that the small heat shock protein gene family coordinately plays an important role in motor neuron viability.
Department of Neurology, The Ohio State University Medical Center, Hamilton Hall, Room 337B, 1645 Neil Ave., Columbus, OH 43210-1228, USA. stephen.kolb@osumc.edu
S J
SJ
Kolb
P J
PJ
Snyder
E J
EJ
Poi
E A
EA
Renard
A
A
Bartlett
S
S
Gu
S
S
Sutton
W D
WD
Arnold
M L
ML
Freimer
V H
VH
Lawson
J T
JT
Kissel
T W
TW
Prior
D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006360:Heat-Shock Proteins / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010865:Pilot Projects
C116424:HSPB3 protein, human; D006360:Heat-Shock Proteins