Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response

✍ Scribed by Ines Dierick; Joy Irobi; Sophie Janssens; Jessie Theuns; Robin Lemmens; An Jacobs; Ellen Corsmit; Nicole Hersmus; Ludo Van Den Bosch; Wim Robberecht; Peter De Jonghe; Christine Van Broeckhoven; Vincent Timmerman

• Book ID: 102266845
• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 289 KB
• Volume: 28
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.9503

✦ Synopsis

The 27kDa 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 stressinduced 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 nonneuronal cells. Following heat shock, the HSE variant attenuated significantly the stressrelated 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.