Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response.
The 27 kDa heat shock protein 1 (HSP27) is a member of the ubiquitously expressed small heat shock protein family and has pleiotropic cytoprotective functions. Since HSP27 may act as a motor neuron survival factor, we analyzed the genetic contribution of the human HSPB1 gene (HSPB1) to the etiology of amyotrophic lateral sclerosis (ALS). In a cohort of sporadic ALS patients, we identified three rare genetic variations and one of which (c.-217T>C) targeted a conserved nucleotide of the Heat Shock Element (HSE) in the HSPB1 promoter. Since binding of Heat Shock Factor 1 (HSF1) to this HSE is essential for stress-induced transcription of HSPB1, we examined the effect of the c.-217C allele on transcriptional activity and HSF binding. The basal promoter activity of the HSPB1 c.-217C mutant allele decreased to 50% as compared to the wild-type promoter in neuronal and non-neuronal cells. Following heat shock, the HSE variant attenuated significantly the stress-related increase in transcription. Electrophoretic mobility shift assays demonstrated a dramatically reduced HSF-binding to the c.-217C mutant allele as compared to the c.-217T wild-type allele. In conclusion, our study underscores the importance of the c.-217T nucleotide for HSF binding and heat inducibility of HSPB1. Therefore, our study suggests that the functional HSPB1 variant may represent a genetic modifier in the pathogenesis of motor neuron disease; however, it is necessary to confirm this HSPB1 variant in additional ALS patients.
Dierick
Ines
I
Peripheral Neuropathy Group, University of Antwerp, Universiteitsplein 1, Antwerpen, Belgium.
Irobi
Joy
J
Janssens
Sophie
S
Theuns
Jessie
J
Lemmens
Robin
R
Jacobs
An
A
Corsmit
Ellen
E
Hersmus
Nicole
N
Van Den Bosch
Ludo
L
Robberecht
Wim
W
De Jonghe
Peter
P
Van Broeckhoven
Christine
C
Timmerman
Vincent
V
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D018869:Heat-Shock Response / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins