Distinct mutations at the same positions of STAT3 cause either loss or gain of function

Chandrasekaran, Prabha; Zimmerman, Ofer; Paulson, Michelle L.; Sampaio, Elizabeth P.; Freeman, Alexandra F.; Sowerwine, Kathryn J.; Hurt, D. L.; Alcántara-Montiel, Julio C.; Hsu, Amy P.; Holland, Steven M.

doi:10.1016/j.jaci.2016.05.007

Cited by 23 publications

(13 citation statements)

References 19 publications

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“…100,112 Interestingly, the same missense mutation can lead to both GOF or LOF, depending on the electrostatic interaction with DNA that affects binding affinity. 98,120 Unlike in patients with STAT1 GOF disease, some GOF mutations in STAT3 did not affect its baseline phosphorylation but increased its transcriptional activity. 100 Dysregulation in B-cell subsets and immunoglobulin levels was frequently observed but highly variable; several patients exhibited lower levels of class-switched immunoglobulin (IgG and IgA) and numbers of memory B cells, 99,100,[115][116][117][118] indicating a potential impairment in B-cell antigen responses.…”

Section: Monogenic Diseases That Affect Foxp3 1 Treg Cell Function: Cmentioning

confidence: 86%

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cepika

Sato

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

114

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Section: Monogenic Diseases That Affect Foxp3 1 Treg Cell Function: Cmentioning

confidence: 86%

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Cepika

Sato

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

114

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“…Severe mutations in STAT3 presented slightly higher frequency of gastrointestinal and endocrine manifestations. Although the presence of these complications was reported before in AD‐HIES, special attention should be paid to differing them from presentation of STAT3 gain‐of‐function variants associated with hypogammaglobulinemia and lymphoproliferative disorders . Diminished T helper 17 (Th17) could be helpful for immunologic diagnosis of HIES patients; however, these data were only available in 6 STAT3‐deficient patients (all <0.5% of total CD4 + T cells) and none of DOCK8‐deficient patients limiting the subcohort analysis.…”

Section: Discussionmentioning

confidence: 99%

The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long‐term follow‐up and genetic analysis

Tavassoli

Abolhassani

Yazdani

et al. 2019

Pediatric Allergy Immunology

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Background Hyper‐IgE syndromes (HIES) are distinct diseases characterized by recurrent cutaneous and lung infections, eczema, and elevated serum IgE level. Methods In this study, clinical manifestations, immunologic findings, and genetic studies of all patients with HIES in the Iranian national registry database were evaluated. Results A total of 129 HIES patients with a median age of 14.0 (9.0‐24.0) years were followed up for a total of 307.8 patient‐years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3‐deficient patients was higher than in patients with DOCK8 mutation (P = 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3‐deficient cases compared to patients with DOCK8 deficiency (P = 0.001 and P = 0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than in patients with DOCK8 gene mutation (P = 0.02). The eosinophils’ count was enhanced in patients with DOCK8 deficiency than in patients with STAT3 gene defects (P = 0.02). Conclusion Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency, investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities.

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“…All seven STATs form homo-and heterodimers following phosphorylation of their tyrosine residues, and thus there is great potential for dominant effects in which only one partner is mutated. These mutations can affect many different protein-protein interactions, leading to dominant phenotypes that reflect either loss of function (LOF) or gain of function (GOF), as summarized recently for STAT3 (Chandrasekaran et al 2016). However, STAT mutations will be manifest in human disease only if they lead to a discernable biological phenotype and, although many dominant mutations have been described for STAT1 and STAT3, far fewer have emerged for the other STATs.…”

Section: Jak and Stat Mutations Naturally Occurring Stat Mutationsmentioning

confidence: 99%

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. Because the basic biochemistry of Janus kinase -signal transducers and activators of transcription (JAK-STAT) signaling pathways has been frequently and extensively reviewed (see, for example, Stark and Darnell 2012;Cai et al. 2015;O'Shea et al. 2015;Villarino et al. 2015), we present here only a brief summary. After a cytokine or interferon binds to its specific receptor, the receptor forms homodimers, heterodimers, or trimers, depending on the cytokine, thus activating the tightly bound JAKs to cross-phosphorylate each other. The activated JAKs then phosphorylate specific tyrosine residues in the cytoplasmic domains of the receptors, providing binding sites for the STATs through their highly conserved SH2 domains. The receptor-bound STATs are phosphorylated, each on a highly conserved tyrosine residue, after which they leave the receptor as homo-or heterodimers whose association is strengthened by SH2-phosphotyrosine interactions. The phosphorylated STAT dimers are then transported to the nucleus, where they bind to and activate specific promoters. The basic outline of JAK-STAT signaling (Fig. 1) shows that interferon (IFN)-g (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-b and the subtypes of IFN-a (collectively type I IFNs) and the subtypes of IFN-l (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form in-

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Distinct mutations at the same positions of STAT3 cause either loss or gain of function

Cited by 23 publications

References 19 publications

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

The first cohort of Iranian patients with hyper immunoglobulin E syndrome: A long‐term follow‐up and genetic analysis

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

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