Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity

Jägle, Sabine; Heeg, Maximilian; Grün, Sarah; Rensing‐Ehl, Anne; Maccari, Maria Elena; Klemann, Christian; Jones, Neil D.; Lehmberg, Kai; Bettoni, C; Warnatz, Klaus; Grimbacher, Bodo; Biebl, Ariane; Schauer, U.; Hague, Rosie; Neth, Olaf; Mauracher, Andrea A.; Schmid, Jana Pachlopnik; Fabre, Alexandre; Kostyuchenko, Larysa; Führer, Marita; Lorenz, Myriam Ricarda; Schwarz, Klaus; Rohr, Jan; Ehl, Stephan

doi:10.1016/j.clim.2019.108316

Cited by 44 publications

(66 citation statements)

References 33 publications

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“…After genetic counseling, the family decided against mutation analysis of further family members. The patient's missense mutation leads to increased transcription of STAT3 but does not change phosphorylation (data not shown) and was observed in another patient of our cohort and functionally analyzed within our AL-PID study [2]. STAT3-GOF (OMIM #15952) is an IEI activating signal transduction and thus leading to often early-onset multi-organ autoimmunity.…”

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confidence: 56%

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Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient

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confidence: 56%

“…The phenotype and penetrance are highly variable. Eighty-three percent of patients have hematologic involvement, mostly in the form of autoimmune cytopenia and often in combination (57% ITP, 45% AIHA, 21% autoimmune neutropenia) [ 2 ]. STAT3-GOF causes pathological lymphoproliferation in around two-thirds of patients.…”

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confidence: 99%

Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient

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“…Key disease-associated components of its structure include a highly-conserved SH2 domain and a DNA-binding domain (DBD), both implicated in loss-of-function and gain-offunction (GOF) syndromes. While DN STAT3 mutations cause STAT3-HIES, the phenotype of GOF mutations varies: somatic mutations are associated with large granular lymphocytic leukemia [100] and germline mutations with a variable syndrome of early-onset multiorgan autoimmunity and lymphoproliferation [101,102]. Mutations causing STAT3-HIES and STAT3-GOF may affect the same codon [3,103].…”

Section: Genetics Of Stat3mentioning

confidence: 99%

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

2021

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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 transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.

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“…The CCD mediates the interaction of STAT‐3 with cytokine receptors and is required for subsequent STAT‐3 phosphorylation [ 15 ]. Germline GOF variants are found throughout the protein except the N‐terminal domain, and several patients with STAT‐3 GOF variant affecting the CCD of STAT‐3 were reported [ 10 , 11 , 16 ]. STAT‐3 GOF has also been found in association with common variable immunodeficiency and three of the four variants described lie within the CCD [ 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Novel STAT-3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype

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Kállai

et al. 2021

Clinical and Experimental Immunology

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Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity

Cited by 44 publications

References 33 publications

Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient

Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient

STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions

Novel STAT-3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype

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