A partial form of recessive STAT1 deficiency in humans

Chapgier, Ariane; Kong, Xiao‐Fei; Boisson–Dupuis, Stéphanie; Jouanguy, Emmanuelle; Averbuch, Diana; Feinberg, Jacqueline; Zhang, Shen-Ying; Bustamante, Jacinta; Vogt, Guillaume; Lejeune, Julien; Mayola, Eléonore; Beaucoudrey, Ludovic de; Abel, Laurent; Engelhard, Dan; Casanova, Jean‐Laurent

doi:10.1172/jci37083

Cited by 175 publications

(128 citation statements)

References 52 publications

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“…Patients with the autosomal recessive partial form of STAT1 deficiency presented severe but curable intracellular bacterial and viral diseases, and these patients showed reduced but not abolished responses to both IFN-␥ and IFN-␣ and weaker STAT1 DNA-binding activity. 14,16 The divergence between the severe defects in the biologic response to IFN-␥ and IFN-␣ and the preserved expression and tyrosine phosphorylation of STAT1 might be related to the effects of the novel splicing mutation. Analysis of the N-terminal domain has shown that this region is characterized by a well-defined hydrophobic core that is highly conserved across the STAT proteins.…”

Section: Stat1 Splicing Mutation Leads To Severe Phenotype 1813mentioning

confidence: 99%

“…3,4 Partial STAT1 deficiency is inherited as an autosomal recessive or autosomal dominant disease. [13][14][15][16] Patients with heterozygous mutations of STAT1, unlike patients who are homozygous, display an impaired tyrosine phosphorylation or DNA-binding activity in response to IFN-␥ but retain a normal or partial response to IFN-␣ and are not susceptible to viral disease. 13,15,17 We describe here a patient with homozygous STAT1 splicing mutation leading to skipping of exon 3 who developed generalized mycobacterial infections and severe viral disease sustained by CMV.…”

Section: Introductionmentioning

confidence: 99%

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Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

Vairo¹,

Tassone²,

Tabellini

et al. 2011

Blood

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IntroductionMendelian predisposition to mycobacterial diseases is characterized by the occurrence of clinically evident infectious episodes sustained by weakly virulent mycobacteria or salmonellae in patients with no other infections. These inherited conditions are caused by germline mutations affecting genes involved in the IFN-␥ and IL-12 signaling pathways. 1,2 However, complete Signal Transducer and Activator of Transcription 1 (STAT1) deficiency is more severe than other deficiencies in IFN-␥ receptor 1 (IFN-␥R1) or IFN-␥ receptor 2 (IFN-␥R2) because STAT1 signaling is common to many transduction pathways and affects not only IFN-␥. [3][4][5] Indeed, STAT1 is also required for the cellular response to many cytokines with antiviral activities, such as IFN-␣/␤/1 or cytokines with immunomodulatory functions on natural killer (NK) and B cells, such as IL-15, IL-21, and IL-27. [6][7][8] After type I IFN stimulation, the receptor is phosphorylated by Janus kinases JAK1 and TYK2, leading to subsequent docking and phosphorylation of both STAT1 and STAT2. Active STAT1/STAT2 heterodimers are released into the cytosol and translocate to the nucleus, where they bind to type I IFN-stimulated response elements (ISREs) in the promoter of target genes. 9,10 Stimulation with IFN-␥ leads to activation of the Janus kinase JAK1 and JAK2, which create a docking site for 2 STAT1 molecules, which are phosphorylated and released into the cytosol as active STAT1 homodimers. The active complex translocates to the nucleus where it binds to the IFN-␥ response region (GRR). 9,11,12 Complete STAT1 deficiency, inherited as an autosomal recessive trait, is characterized by complete lack of STAT1 expression and abolition of STAT1-dependent responses to both IFN-␥ and IFN-␣. These subjects display profound susceptibility to infections with intracellular pathogens and viruses, including life-threatening infections caused by herpes simplex virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). 3,4 Partial STAT1 deficiency is inherited as an autosomal recessive or autosomal dominant disease. [13][14][15][16] Patients with heterozygous mutations of STAT1, unlike patients who are homozygous, display an impaired tyrosine phosphorylation or DNA-binding activity in response to IFN-␥ but retain a normal or partial response to IFN-␣ and are not susceptible to viral disease. 13,15,17 We describe here a patient with homozygous STAT1 splicing mutation leading to skipping of exon 3 who developed generalized mycobacterial infections and severe viral disease sustained by CMV. We report that the patient's cells display a complete defect of STAT1 DNA-binding activity after stimulation with IFN-␥ and IFN-␣ and fail to respond at even high doses of these cytokines. These biologic defects are associated with a partial impairment of NK functional activity, which might contribute to the susceptibility of the patient to infections with viral and intracellular pathogens. The online version of this article contains a data supplement.The publication costs of thi...

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Section: Stat1 Splicing Mutation Leads To Severe Phenotype 1813mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

Vairo¹,

Tassone²,

Tabellini

et al. 2011

Blood

View full text Add to dashboard Cite

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“…Phospho-flow can be used in the diagnostic evaluation of PIDs associated with defects in the STAT (signal transducer and activator of transcription factor) molecules, e.g., loss-of-function (LOF) STAT1 mutations seen in patients with susceptibility to intracellular bacterial and viral infections (72,73). Similarly, gain-of-function (GOF) mutations seen in the same gene, STAT1, associated with autosomal dominant chronic mucocutaneous candidiasis (CMC) and defective Th17 immunity (74)(75)(76)(77)(78) can also be assessed by changes in phosphorylation by flow cytometry.…”

Section: Functional Flow Cytometry For Disease-specific Pids and Immumentioning

confidence: 99%

Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

Abraham

Aubert

2016

Clin Vaccine Immunol

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bGenetic defects of the immune system are referred to as primary immunodeficiencies (PIDs). These immunodeficiencies are clinically and immunologically heterogeneous and, therefore, pose a challenge not only for the clinician but also for the diagnostic immunologist. There are several methodological tools available for evaluation and monitoring of patients with PIDs, and of these tools, flow cytometry has gained prominence, both for phenotyping and functional assays. Flow cytometry allows real-time analysis of cellular composition, cell signaling, and other relevant immunological pathways, providing an accessible tool for rapid diagnostic and prognostic assessment. This minireview provides an overview of the use of flow cytometry in disease-specific diagnosis of PIDs, in addition to other broader applications, which include immune phenotyping and cellular functional measurements.

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“…Patients with this disease suffer from both severe viral infections (herpes viruses), as well as intracellular pathogens (Salmonella, BCG, and nontuberculous mycobacteria). 12 Interestingly, gain of function autosomal dominant STAT1 mutations can develop infections similar to those with loss of function mutations but can also develop infections with dimorphic molds (Samplaio et al 13 ) as well as CMC and autoimmunity (Uzel et al 14 ). Although these patients have increased expression of cytokines that promote Th17 immune deviation (IL-6 and IL-21), ultimately, the stronger cellular responses to the STAT-1 activating cytokines IFN-␣/␤, IFN-␥, and IL-27 prevail, and their Th1 immune deviating influences supersede and hinder the development of Th17 cells.…”

Section: Question 1 What Is the Differential Diagnosis Of Cmc?mentioning

confidence: 99%

Fifty-five-year-old man with chronic yeast infections

Kennedy

Schroeder²,

Palacios³

et al. 2014

allergy asthma proc

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As History of Present IllnessA 55-year-old man was referred to the University of Virginia Immunology Clinic for onychodystrophy of his fingernails and toenails and recurrent oral-esophageal candidiasis. He had the problem with his toenails since childhood, but this had subsequently spread to involve his fingernails ϳ4 -5 years ago. Six months previously, he was diagnosed with oral candidiasis and was successfully treated with nystatin. He had no history of antibiotic or corticosteroid usage. One week later, he again developed thrush, and this pattern continued over the next months. Concomitantly, he was evaluated by the Dermatology Department for the onychodystrophy. Fingernail cultures were positive for Candida and his toenails grew dematiaceous mold. He was treated with fluconazole or itraconazole at various times over the past year and noted improvement with these treatments. Again, once the medications were removed, his symptoms returned. His last course of antifungal medication was completed 2 weeks before presenting to our clinic.During our evaluation, he reported early dysphagia, especially while eating bread. He also described symptoms of gastroesophageal reflux and cough that were persistent and exacerbated after both eating and exercising. The cough would resolve with his ongoing antiyeast treatments. He denied constitutional symptoms as well as sinopulmonary, gastrointestinal, blood, bone, central nervous system, or kidney infections. He denied recurrent herpes, varicella, or human papilloma virus infections. Most importantly, he denied infections with Staphylococcus aureus including furunculosis. He had no history of autoimmune disease such as thyroiditis, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura, although he did report transverse myelitis that developed temporally to receiving the tetanus and influenza vaccinations, ϳ17 years before presenting to our clinic. He had no human immunodeficiency virus (HIV) risk factors. Physical ExaminationOn physical examination his oropharynx was without evidence of oral candidiasis. He had no lymphadenopathy and his respiratory exam was normal. Skin examination did not show atopic dermatitis or furunculosis; however, he had significant onychodystrophy of his fingernails and toenails. Laboratory and Other Diagnostic FindingsOur initial immunologic evaluation showed absent delayed-type hypersensitivity testing to Candida and

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A partial form of recessive STAT1 deficiency in humans

Cited by 175 publications

References 52 publications

Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

Fifty-five-year-old man with chronic yeast infections

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