Novel signal transducer and activator of transcription 1 mutation disrupts small ubiquitin-related modifier conjugation causing gain of function

Sampaio, Elizabeth P.; Ding, Li; Rose, Stacey; Cruz, Phillip; Hsu, Amy P.; Kashyap, Anuj; Rosen, Lindsey B.; Smelkinson, Margery; Tavella, Tatyana Almeida; Ferré, Elise M. N.; Wierman, Meredith K.; Zerbe, Christa S.; Lionakis, Michail S.; Holland, Steven M.

doi:10.1016/j.jaci.2017.07.027

Cited by 19 publications

(21 citation statements)

References 38 publications

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“…Demodicidosis or rosacea were reported in some patients ( n = 5) ( 19 – 21 ). One patient suffered from Norwegian scabies ( 22 ). The JC virus, Demodicidosis, Norwegian scabies were not recorded in previous review ( 7 ).…”

Section: Resultsmentioning

confidence: 99%

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

et al. 2021

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Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled.Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions.Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed.Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection.Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

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Section: Resultsmentioning

confidence: 99%

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

et al. 2021

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“…Of note, chronic Candida infections of the oral and esophageal mucosal surfaces can lead to the development of oral or esophageal squamous cell carcinomas in ~5% of adult patients with long‐standing mucosal candidiasis . Carcinoma development in the context of monogenic disorders that manifest with CMC is not only restricted to APECED, but can also be seen in patients with STAT1 gain‐of‐function mutations . The mechanisms for this susceptibility to neoplasm development remain unclear, but may relate to enhanced EGFR signaling triggered by autoreactive CD4 + T cells in the epithelial barrier .…”

Section: Clinical Manifestations Of Apeced Patientsmentioning

confidence: 99%

“…42,43 Carcinoma development in the context of monogenic disorders that manifest with CMC is not only restricted to APECED, but can also be seen in patients with STAT1 gain-of-function mutations. 44,45 The mechanisms for this susceptibility to neoplasm development remain unclear, but may relate to enhanced EGFR signaling triggered by autoreactive CD4 + T cells in the epithelial barrier. 46 Candidiasis may also affect the intestinal or vaginal mucosal surfaces or the nails in APECED patients, albeit with much lower frequencies compared to the oral and esophageal mucosa, while involvement of the skin is very uncommon (Lionakis, unpublished observations).…”

Section: Infectious Manifestationsmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

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122

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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“…Phosphorylated STAT1 protein directly binds the DNA and regulates cellular immunity involving Th17 cells and associated cytokines including IL-17, which are thought to play a role in immunity against mucocutaneous candidiasis. 3,15–17 STAT1 GOF mutations cause hyperphosphorylation of STAT1 protein and dysregulate this processes, resulting in decreased number of Th17 cells. This suggests a possible mechanism behind mucocutaneous candidiasis in these patients and the clinical benefits seen in these patients from ruxolitinib by blocking the phosphorylation of STAT1 (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…This suggests a possible mechanism behind mucocutaneous candidiasis in these patients and the clinical benefits seen in these patients from ruxolitinib by blocking the phosphorylation of STAT1 (Figure 4). 3,13,15,18…”

Section: Discussionmentioning

confidence: 99%

Bronchiectasis and Bronchiolectasis With Severe Herniating Pattern Associated With STAT1 Gain-of-Function Mutation: Detailed Clinicopathological Findings

et al. 2021

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STAT1 gain-of-function (GOF) mutations are associated with a rare autosomal dominant immunodeficiency disorder with main clinical manifestations including chronic mucocutaneous candidiasis (CMC) and bronchiectasis. In addition, these patients show higher incidences of cerebral and extracerebral aneurysm, malignancies and various autoimmune conditions compared to the general population. Although previous publications have reported clinical findings in patients with STAT1 GOF mutation, they did not include histopathologic features. Herein, we describe the first case with detailed histologic findings in the lung of a 5-year-old patient with a de novo STAT1 GOF mutation, who presented with CMC and bronchiectasis. The biopsy showed severe bronchiolectasis with extensive airway dilatation and occasional disruptions. Peribronchiolar inflammation was not always present and evident mainly in areas of airway disruption; inflammation may have not been a main driver of the airway damage in this case. The airway dilatation often showed an interesting herniating pattern, possibly implying a connective tissue etiology. This case also demonstrates the diagnostic utility of whole exome sequencing as STAT1 GOF mutations are not detected by routine workup. The definitive diagnosis will lead to more specific treatments and increased surveillance for serious conditions, such as cerebral aneurysms and malignancies.

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Novel signal transducer and activator of transcription 1 mutation disrupts small ubiquitin-related modifier conjugation causing gain of function

Abstract: This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects.

Cited by 19 publications

References 38 publications

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Bronchiectasis and Bronchiolectasis With Severe Herniating Pattern Associated With STAT1 Gain-of-Function Mutation: Detailed Clinicopathological Findings

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