|
Title
|
|
|
|
Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response
| |
|
Author
|
|
|
|
| |
|
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 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. (C) 2007 Wiley-Liss, Inc. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Human mutation. - New York, N.Y.
| |
|
Publication
|
|
|
|
New York, N.Y.
:
2007
| |
|
ISSN
|
|
|
|
1059-7794
| |
|
DOI
|
|
|
|
10.1002/HUMU.9503
| |
|
Volume/pages
|
|
|
|
28
:8
(2007)
, p. 830
| |
|
ISI
|
|
|
|
000248748300011
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|