Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.

Authors: Minegishi, Y  Saito, M  Tsuchiya, S  Tsuge, I  Takada, H  Hara, T  Kawamura, N  Ariga, T  Pasic, S  Stojkovic, O  Metin, A  Karasuyama, H 
Citation: Minegishi Y, etal., Nature. 2007 Aug 30;448(7157):1058-62. Epub 2007 Aug 5.
Pubmed: (View Article at PubMed) PMID:17676033
DOI: Full-text: DOI:10.1038/nature06096

Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

Annotation

Disease Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 6892956
Created: 2012-08-21
Species: All species
Last Modified: 2012-08-21
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.