scholarly journals Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Vivien Béziat ◽  
Simon J. Tavernier ◽  
Yin-Huai Chen ◽  
Cindy S. Ma ◽  
Marie Materna ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Mutant Proteins ◽  
Skeletal Abnormalities ◽  
Tyrosine Residues ◽  
Hyper Ige Syndrome ◽  
Dominant Negative Mutations ◽  
Allergic Manifestations ◽  
Stat3 Mutations

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

scholarly journals A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

2019 ◽  
Vol 116 (33) ◽  
pp. 16463-16472 ◽  
Author(s):  
Joëlle Khourieh ◽  
Geetha Rao ◽  
Tanwir Habib ◽  
Danielle T. Avery ◽  
Alain Lefèvre-Utile ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Loss Of Function ◽  
Wild Type ◽  
Dominant Form ◽  
Mutant Proteins ◽  
Coding Regions ◽  
Hyper Ige Syndrome ◽  
Autosomal Dominant Form ◽  
Negative Dominance ◽  
B And T Lymphocytes

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 responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal 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 involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

scholarly journals Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion

Blood ◽  
2015 ◽  
Vol 125 (10) ◽  
pp. 1566-1577 ◽  
Author(s):  
Waldo A. Spessott ◽  
Maria L. Sanmillan ◽  
Margaret E. McCormick ◽  
Nishant Patel ◽  
Joyce Villanueva ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Dominant Negative ◽  
Snare Complex ◽  
Complex Assembly ◽  
Mutant Proteins ◽  
Key Points ◽  
Lymphocyte Cytotoxicity ◽  
Dominant Negative Mutations

Key Points Monoallelic STXBP2 mutations affecting codon 65 impair lymphocyte cytotoxicity and contribute to hemophagocytic lymphohistiocytosis. Munc18-2R65Q/W mutant proteins function in a dominant-negative manner to impair membrane fusion and arrest SNARE-complex assembly.

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

Nature ◽  
2007 ◽  
Vol 448 (7157) ◽  
pp. 1058-1062 ◽  
Author(s):  
Yoshiyuki Minegishi ◽  
Masako Saito ◽  
Shigeru Tsuchiya ◽  
Ikuya Tsuge ◽  
Hidetoshi Takada ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Domain ◽  
Dominant Negative ◽  
Dna Binding Domain ◽  
Hyper Ige Syndrome ◽  
Dominant Negative Mutations

scholarly journals Caenorhabditis elegans SUR-5, a Novel but Conserved Protein, Negatively Regulates LET-60 Ras Activity during Vulval Induction

1998 ◽  
Vol 18 (8) ◽  
pp. 4556-4564 ◽  
Author(s):  
Trent Gu ◽  
Satoshi Orita ◽  
Min Han
Keyword(s):  
Caenorhabditis Elegans ◽  
Sequence Similarity ◽  
Signal Transduction Pathway ◽  
Specific Aspect ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Negative Function ◽  
Ras Activation ◽  
Dominant Negative Mutations ◽  
Novel Protein

ABSTRACT The let-60 ras gene acts in a signal transduction pathway to control vulval differentiation in Caenorhabditis elegans. By screening suppressors of a dominant negativelet-60 ras allele, we isolated three loss-of-function mutations in the sur-5 gene which appear to act as negative regulators of let-60 ras during vulval induction.sur-5 mutations do not cause an obvious mutant phenotype of their own, and they appear to specifically suppress only one of the two groups of let-60 ras dominant negative mutations, suggesting that the gene may be involved in a specific aspect of Ras activation. Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activatedlet-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation. We have clonedsur-5 and shown that it encodes a novel protein. We have also identified a potential mammalian SUR-5 homolog that is about 35% identical to the worm protein. SUR-5 also has some sequence similarity to acetyl coenzyme A synthetases and is predicted to contain ATP/GTP and AMP binding sites. Our results suggest thatsur-5 gene function may be conserved through evolution.

Mutagenesis of Ste18, a putative Gγ subunit in the Saccharomyces cerevisiae pheromone response pathway

1992 ◽  
Vol 70 (10-11) ◽  
pp. 1230-1237 ◽  
Author(s):  
Malcolm Whiteway ◽  
Daniel Dignard ◽  
David Y. Thomas
Keyword(s):  
Signal Transduction ◽  
Dominant Negative ◽  
Saturation Mutagenesis ◽  
Pheromone Response ◽  
Mutant Proteins ◽  
Pheromone Response Pathway ◽  
Allele Specific ◽  
Dominant Negative Mutations ◽  
Compensatory Mutations ◽  
Mutant Genes

The yeast STE18 gene product has sequence and functional similarity to the γ subunits of G proteins. The cloned STE18 gene was subjected to a saturation mutagenesis using doped oligonucleotides. The populations of mutant genes were screened for two classes of STE18 mutations, those that allowed for increased mating of a strain containing a defective STE4 gene (compensators) and those that inhibited mating even in the presence of a functional STE18 gene (dominant negatives). Three amino acid substitutions that enhanced mating in a specific STE4 (Gβ) point mutant background were identified. These compensatory mutations were allele specific and had no detectable phenotype of their own; they may define residues that mediate an association between the Gβ and Gγ subunits or in the association of the Gβγ subunit with other components of the signalling pathway. Several dominant negative mutations were also identified, including two C terminal truncations. These mutant proteins were unable to function in signal transduction by themselves, but they prevented signal transduction mediated by pheromone, as well as the constitutive signalling which is present in cells defective in the GPAI (Gα) gene. These mutant proteins may sequester Gβ or some other component of the signalling machinery in a nonfunctional complex. Key wordsi yeast, G protein, STE18, mutagenesis, pheromone response.

scholarly journals Treatment approaches to hyper-IgE syndrome: a clinical case report

2019 ◽  
Vol 17 (4) ◽  
pp. 75-81
Author(s):  
A. K. Kantulaeva ◽  
N. B. Kuzmenko ◽  
E. V. Deripapa ◽  
D. V. Yukhacheva ◽  
E. A. Victorova ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antimicrobial Prophylaxis ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome ◽  
Bioactive Agents ◽  
Bone Anomalies ◽  
Risk Of Cancer ◽  
Transcription 3

The hyper-IgE syndrome with dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3) gene is a combined primary immunodeficiency characterized by severe bacterial infections (skin and lungs with bullae formation), characteristic phenotype, serum IgE elevation, eosinophilia, as well as connective tissue, and bone anomalies. Patients also have  high risk of cancer. STAT3 is a transcription factor important for the JAK/STAT signaling pathway, which plays the key role in the synthesis of cytokines, hormones, and bioactive agents. Hyper-IgE syndrome therapy includes antimicrobial prophylaxis, immunoglobulin replacement, and use of bisphosphonates. Hematopoietic stem cell transplantation is an alternative way for the disease treatment. Here we describe a patient with severe autosomal dominant hyper-IgE-syndrome with thte loss-of-function mutation in the STAT3 gene. Patient's parents agreed to use personal dats and photos in research and publications.

scholarly journals Dental abnormalities in a patient with autosomal dominant hyper-IgE syndrome: A case control study

2021 ◽  
Author(s):  
Marziyeh Heidarzadeh ◽  
Atena Ramezanali Yakhchali ◽  
Mohammad Gharagozlou ◽  
Sepideh Darougar ◽  
Zahra Chavoshzadeh ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Case Control Study ◽  
Elevated Serum ◽  
Dominant Negative ◽  
Hyper Ige Syndrome ◽  
Dental Abnormality ◽  
Eczematous Dermatitis ◽  
Dominant Negative Mutations ◽  
Tissue Defects ◽  
Control Study

Autosomal-dominant hyper-IgE (AD-HIES) is mainly characterized by eczematous dermatitis, staphylococcal skin abscesses, connective tissue defects, and elevated serum IgE. This disorder is largely associated with heterozygous dominant-negative mutations in STAT3 gene. Herein, we reported a patient with AD-HIES suffering from dental abnormality and allergic reactions.

Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3229-3240 ◽  
Author(s):  
S.I. Osada ◽  
C.V. Wright
Keyword(s):  
Early Embryogenesis ◽  
Dominant Negative ◽  
Mesoderm Induction ◽  
Loss Of Function ◽  
Related Factors ◽  
Mutant Proteins ◽  
Organizer Activity ◽  
The Relationship ◽  
Protein Treatment ◽  
Transcript Induction

Previously, we showed that Xenopus nodal-related factors (Xnrs) can act as mesoderm inducers, and that activin induces Xnr transcription, suggesting that Xnrs relay or maintain induction processes initiated by activin-like molecules. We used a dominant negative cleavage mutant Xnr2 (cmXnr2) to carry out loss-of-function experiments to explore the requirement for Xnr signaling in early amphibian embryogenesis, and the relationship between activin and Xnrs. cmXnr2 blocked mesoderm induction caused by Xnr, but not activin, RNA. In contrast, cmXnr2 did suppress mesoderm and endoderm induction by activin protein, while Xnr transcript induction was unaffected by cmXnr2, consistent with an interference with the function of Xnr peptides that were induced by activin protein treatment. The severe hyperdorsalization and gastrulation defects caused by Xnr2 in whole embryos were rescued by cmXnr2, establishing a specific antagonistic relationship between the normal and cleavage mutant proteins. Expression of cmXnr2 resulted in delayed dorsal lip formation and a range of anterior truncations that were associated with delayed and suppressed expression of markers for dorsoanterior endoderm, in which the recently recognized head organizer activity resides. Reciprocally, Xnr2 induced dorsoanterior endodermal markers, such as cerberus, Xhex-1 and Frzb, in animal cap ectoderm. The migratory behavior of head mesendoderm explanted from cmXnr2 RNA-injected embryos was drastically reduced. These results indicate that Xnrs play crucial roles in initiating gastrulation, probably by acting downstream of an activin-like signaling pathway that leads to dorsal mesendodermal specification, including setting up the head organizer.

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