Related Papers
Journal of Clinical Immunology
STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions
2021 •
Alexandra Freeman
The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplan...
Molecular Immunology
A novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene, in hyper-IgE syndrome
2010 •
Stefanos Mantagos
Blood
Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome
2016 •
David Tweardy
AD-HIES is caused by dominant negative mutations in STAT3; however, the molecular basis for mutant STAT3 allele dysfunction is unclear and treatment remains supportive. We hypothesized that AD-HIES mutations decrease STAT3 protein stability and that mutant STAT3 activity can be improved by agents that increase chaperone protein activity. We used computer modeling to characterize the effect of STAT3 mutations on protein stability. We measured STAT3 protein half-life (t1/2) and determined levels of STAT3 phosphorylated on tyrosine (Y) 705 (pY-STAT3) and mRNA levels of STAT3 gene targets in EBV-transformed B (EBV) cells, human peripheral blood mononuclear cells (PBMC), and mouse splenocytes incubated without or with chaperone protein modulators-HSF1A, a small-molecule TRiC modulator, or geranylgeranylacetone (GGA), a drug that upregulates heat shock protein (HSP) 70 and HSP90. Computer modeling predicted that 81% of AD-HIES mutations are destabilizing. STAT3 protein t1/2 in EBV cells f...
Journal of Clinical Immunology
Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome
2021 •
Waleed Al-herz
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involveme...
Proceedings of the National Academy of Sciences
A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance
2019 •
Anne Puel
Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes resp...
Experimental hematology
CRISPR-mediated Genotypic and Phenotypic Correction of a Chronic Granulomatous Disease mutation in human iPS cells
2015 •
William James
Chronic Granulomatous Disease (CGD) is a rare genetic disease characterised by severe and persistent childhood infections. It is caused by the lack of an "anti-pathogen" oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses, with concomitant issues of insertional mutagenesis, inaccurate gene dosage and gene silencing. Here we explore the potential of the recently described CRISPR-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of hom*ologous recombination. Using induced Pluripotent Stem cells derived from a CGD patie...
Molecular Immunology
Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups
2008 •
Lennart Hammarström
Molecular Therapy
Efficient and Allele-Specific Genome Editing of Disease Loci in Human iPSCs
2014 •
Cory Smith
Nature
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome
2007 •
Oliver Stojkovic
Genes to Cells
Genome editing in induced pluripotent stem cells
2012 •
Ofer Binah
