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.
Kolb
S J
SJ
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
Snyder
P J
PJ
Poi
E J
EJ
Renard
E A
EA
Bartlett
A
A
Gu
S
S
Sutton
S
S
Arnold
W D
WD
Freimer
M L
ML
Lawson
V H
VH
Kissel
J T
JT
Prior
T W
TW
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