title: Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response.
abstract: 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.
authors.affiliation: Peripheral Neuropathy Group, University of Antwerp, Universiteitsplein 1, Antwerpen, Belgium.
authors.forename: Ines
authors.initials: I
authors.lastname: Dierick
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Sophie
authors.initials: S
authors.lastname: Janssens
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: An
authors.initials: A
authors.lastname: Jacobs
authors.forename: Ellen
authors.initials: E
authors.lastname: Corsmit
authors.forename: Nicole
authors.initials: N
authors.lastname: Hersmus
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: 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
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins