| 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
| |
| Volume/pages |
|
|
|
28:8(2007), p. 830
| |
| ISI |
|
|
|
000248748300011
| |
| Full text (Publisher's DOI) |
|
|
| | |
|