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Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response
Author(s) -
Dierick Ines,
Irobi Joy,
Janssens Sophie,
Theuns Jessie,
Lemmens Robin,
Jacobs An,
Corsmit Ellen,
Hersmus Nicole,
Van Den Bosch Ludo,
Robberecht Wim,
De Jonghe Peter,
Van Broeckhoven Christine,
Timmerman Vincent
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9503
Subject(s) - biology , hsf1 , heat shock protein , heat shock factor , hsp27 , genetics , transcription factor , allele , heat shock , mutant , microbiology and biotechnology , promoter , gene , hsp70 , gene expression
Abstract 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 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. Published 2007 Wiley‐Liss, Inc.