scholarly journals Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
Takaki Asano ◽  
Joëlle Khourieh ◽  
Peng Zhang ◽  
Franck Rapaport ◽  
András N. Spaan ◽  
...  
Keyword(s):  
General Population ◽  
Autosomal Dominant ◽  
Dominant Negative ◽  
Alternative Transcripts ◽  
Hyper Ige Syndrome ◽  
Negative Dominance

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

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.

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.

Abstract 618: Hypoxia Inducible Factor 1a Stabilization in Autosomal Dominant Hyper IgE Syndrome Fibroblasts Rescues Impaired Ability to Support Angiogenesis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Alex F Grubb ◽  
Natalia I Dmitrieva ◽  
Avram Walts ◽  
Guibin Chen ◽  
Xue Zhang ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Pathway Analysis ◽  
Autosomal Dominant ◽  
Hypoxia Inducible Factor ◽  
Tube Formation ◽  
Dominant Negative ◽  
Hyper Ige Syndrome ◽  
Impaired Ability

Background: Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency caused by dominant negative mutations in signal transducer and activator of transcription 3 (STAT3 ) , a mediator of widespread physiological processes. It is characterized by dermatitis, recurrent infections, elevated IgE, poor post-surgical healing, and connective tissue abnormalities. How STAT3 deficiency leads to this phenotype, however, is not known. Current treatment options are limited to antimicrobials for infection control. The aim of this study was to investigate which of STAT3’s many functions are dis-regulated in AD-HIES, and where potential targets for therapy may lie. Methods: We used skin fibroblasts (SF) from 3 AD-HIES patients and 3 normal volunteers. To evaluate potentially affected pathways, we utilized RNA- Seq and subsequent Gene Set Enrichment (GSEA) and pathway analysis (Pathway Studio, GeneGo Metacore). Endothelial cell tube formation assay was used to assess ability of AD-HIES SFs to support angiogenesis. Results: GSEA and pathway analysis showed deficiencies in signaling pathways linked to wound healing, extracellular matrix remodeling and angiogenesis including targets of Hypoxia Inducible Factor 1a (HIF1a) (P values for enrichments < 0.001) . Therefore, we hypothesized that AD-HIES SFs have impaired ability to support angiogenesis due to deficient Hif1a-dependent secretion of matrix proteases and growth factors. Indeed, AD-HIES SF secreted up to 5 times less matrix metalloprotease 1, 3, and 9, placental growth factor and fibroblast growth factors 1 and 2 (Luminex Multiplex, n=3-9, P<0.05). Culture medium from AD-HIES SFs failed to fully support tube formation by endothelial cells resulting in lower number of junctions, meshes, and total tubule length (n=6, P<0.005). Stabilization of Hif1a in AD-HIES SFs by prolyl hydroxylase inhibitor dimethyl fumarate restored its transcriptional activity leading to increased number of junctions, meshes, and tubule length (n=12, P<0.05) Conclusion: AD-HIES SFs have deficiencies in pro-angiogenic signaling pathways that lead to decreased growth factor secretion and angiogenesis. Stabilization of HIF1a corrects this deficiency and is an enticing target for future therapy.

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 Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
A. Chin ◽  
S. Balasubramanyam ◽  
C. M. Davis
Keyword(s):  
Autosomal Dominant ◽  
Severe Infection ◽  
Severe Atopic Dermatitis ◽  
Genomic Testing ◽  
Atopic Diseases ◽  
Variants Of Unknown Significance ◽  
Hyper Ige Syndrome ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Multiple Variants

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

scholarly journals Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene

2002 ◽  
pp. 649-656 ◽  
Author(s):  
J Rutishauser ◽  
P Kopp ◽  
MB Gaskill ◽  
TJ Kotlar ◽  
GL Robertson
Keyword(s):  
Diabetes Insipidus ◽  
Autosomal Dominant ◽  
De Novo ◽  
Index Patient ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
Posterior Pituitary ◽  
Recurrent Mutations ◽  
Neurophysin Ii

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

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
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