Journal
BLOOD
Volume 116, Issue 26, Pages 5895-5906Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-04-280586
Keywords
-
Categories
Funding
- Choh-Hao Li Memorial Fund
- Shanghai Educational Development Foundation
- Rockefeller University Center for Clinical and Translational Science [5UL1RR024143]
- Rockefeller University
- Bill and Melinda Gates Foundation
- St Giles Foundation
- Jeffrey Modell Foundation
- Talecris Biotherapeutics
- National Institute of Allergy and Infectious Diseases [1R01AI089970]
- Schlumberger Foundation
- BNP-Paribas Foundation
- Institut Universitaire de France
- European Union [QLK2-CT-2002-0046]
Ask authors/readers for more resources
Autosomal recessive STAT1 deficiency is associated with impaired cellular responses to interferons and susceptibility to intracellular bacterial and viral infections. We report here a new form of partial STAT1 deficiency in 2 siblings presenting mycobacterial and viral diseases. Both carried a homozygous missense mutation replacing a lysine with an asparagine residue at position 201 (K201N) of STAT1. This mutation causes the abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing (by similar to 70%) STAT1 protein levels. The mutant STAT1 proteins are not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into gamma-activating factor and heterotrimerization into ISGF-3, binding to specific DNA elements, and activation of the transcription. Interestingly, the activation of gamma-activating factor and ISGF3 was impaired only at early time points in the various cells from patient (within 1 hour of stimulation), whereas sustained impairment occurs in other known forms of complete and partial recessive STAT1 deficiency. Consequently, delayed responses were normal; however, the early induction of interferon-stimulated genes was selectively and severely impaired. Thus, the early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections. (Blood. 2010;116(26):5895-5906)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available