Autosomal recessive complete signal transducer and activator of transcription 1 deficiency in a newborn: a case report / 中华围产医学杂志

We reported the clinical data of a neonate admitted to the Second Affiliated Hospital (Yuying Children's Hospital) of Wenzhou Medical University in November 2021 with autosomal recessive complete signal transducer and activator of transcription 1 ( STAT1) deficiency identified by whole exome sequencing. The baby boy received bacillus of calmette-guerin (BCG) vaccine 2 d after birth and presented with persistent high fever, increased white blood cell count and increased level of C-reactive protein (CRP) on 21 d after birth. Human cytomegalovirus (HCMV) was detected in both blood and bone marrow specimens. The patient improved after comprehensive treatment with antiviral agents, antibiotics and intravenous gammaglobulin. Oral anti-viral drugs were prescribed on discharge. However, the baby was rehospitalized due to a fever at 55 days. HCMV and Mycobacterium tuberculosis complex were detected in blood samples. The infant was transferred to the Children's Hospital of Fudan University due to persistent high fever even after active management and died after treatment withdrawal at 69 d after birth because of worsening infections and multiple organ failure. A homozygous mutation in the STAT1 gene was detected [c.1011_1012del, NM_007315: exon11: c.1011_1012del (p.V339Pfs*18)] and the child was diagnosed as autosomal recessive complete STAT1 deficiency. We concluded that the clinical manifestations of autosomal recessive complete STAT1 deficiency are bacterial infections caused by lethal low-pathogenic mycobacteria and life-threatening virus infections. Whole exome sequencing is of great value for early diagnosis and timely treatment. The prognosis of this disease is very poor, but the condition of the patients might be improved in a short period with early anti-tuberculosis and anti-viral treatment.

Dermatofitosis por Microsporum gypseum en un niño con inmunodeficiencia primaria / Microsporum gypseum dermatophytosis in a child with primary immunodeficiency

El Microsporum gypseum es un hongo geofílico que puede producir lesiones cutáneas inflamatorias en personas sanas. Se han descripto lesiones más extensas en pacientes inmunocomprometidos. Se presenta el caso de un paciente con dermatofitosis, con exámenes micológicos positivos para Candida sp, Epidermophytom floccosum y Trichophyton tonsurans, al que, ante la mala respuesta al tratamiento con griseofulvina e itraconazol a dosis habituales, se le realizó biopsia cutánea para cultivo que evidenció la presencia de M. gypseum. Debido a la extensión y a la mala respuesta al tratamiento, se realizó evaluación inmunológica y se diagnosticó un defecto en STAT1 con ganancia de función (STAT1-GOF). Los pacientes que tienen esta inmunodeficiencia primaria son susceptibles a las infecciones micóticas, especialmente por Candida, pero también, aunque en menor medida, a virus y bacterias. El paciente aquí presentado recibió tratamiento prolongado con antimicóticos imidazólicos sistémicos, con resolución de las lesiones.

Microsporum gypseum is a geophilic fungus that can cause inflammatory skin lesions in heathy people. More extensive lesions have been described in immunocompromised patients. We present a patient with extensive dermatophytosis, which mycological examination led the identification of Candida sp, Epidermophyton Floccosum and Trichophyton tonsurans and showed poor response to treatment with griseofulvina and itraconazol at usual doses. When skin biopsy was performed, it had positive culture for M. gypseum. Due to the extension and poor response to treatment, immunological assessment was performed and it showed a defect of STAT1 with gain of function (STAT 1-GOF). Patients with primary immunodeficiency are susceptible to fungal infections, especially Candida but also virus and bacteria, although to a lesser extent. The patient received long-term treatment with systemic imidazole antifungal recovering for the lesions.

Gain-of-function STAT1 mutation and visceral leishmaniasis

ABSTRACT Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

Nova mutação no gene STAT1 associada com candidíase mucocutânea crônica / New STAT1 gene mutation associated with chronic mucocutaneous candidiasis

Mutações no gene STAT1 (signal transducer and activator of transcription 1) têm sido identificadas como responsáveis pela maioria dos casos sindrômicos da candidíase mucocutânea crônica com herança autossômica dominante (AD). Nesse artigo, descrevemos uma menina de 7 anos que apresentou candidíase da mucosa oral e unhas, além de infecção disseminada da pele e couro cabeludo por Microspora gipseum. Recentemente, a paciente foi diagnosticada e tratada de meningite por Cryptococcus neoformans. Na família não existem outros casos de candidíase. A avaliação imunológica incluiu a detecção de subpopulações de linfócitos (CD3, CD4, CD8, CD20 e células NK), assim como a dosagem de IgG, IgA, IgM e IgE, subclasses de IgG e autoanticorpos. Excluindo-se discreta diminuição de CD3, CD4, CD8, NK e leve aumento de IgG1, os demais exames estiveram dentro da normalidade. O sequenciamento do exoma detectou uma rara mutação em heterozigose no exon 14 do domínio de ligação do DNA (DNA-binding domain) do gene STAT1, ocasionando um provável ganho de função (GOF) responsável pela doença (Gly384Asp). Essa variação foi também identificada pelo sequenciamento de Sanger, não estando reportada nos bancos de dados públicos e apresentando elevado potencial de dano (índice CADD=32). Será interessante contarmos com informações clínicas e estudos com outros pacientes para conhecermos mais essa mutação patológica. Além da apresentação do caso, discutiremos as formas de tratamento existentes.

STAT1 (signal transducer and activator of transcription 1) gene mutations have been identified as responsible for most syndromic cases of chronic mucocutaneous candidiasis with autosomal dominant (AD) inheritance. In this article, we described a 7-year-old girl who presented with candidiasis of the oral mucosa and nails, as well as disseminated infection of the skin and scalp caused by Microsporum gypseum. Recently, the patient was diagnosed and treated for Cryptococcus neoformans meningitis. There are no other cases of candidiasis in the family. The immunological evaluation consisted of detection of subpopulations of lymphocytes (CD3, CD4, CD8, CD20, and NK cells), as well as measurement of IgG, IgA, IgM, and IgE, IgG subclasses, and autoantibodies. Excluding a slight decrease in CD3, CD4, CD8, NK and a minimal increase in IgG1, the others were within normal limits. Exome sequencing detected a rare heterozygous variation in exon 14 of the DNA-binding domain of the STAT1 gene, causing a probable gain of function (GOF) responsible for the disease (Gly384Asp). This variation was also identified by Sanger sequencing, but it was not reported in public databases and had a high potential for damage (Combined Annotation-Dependent Depletion [CADD] score = 32). Having clinical information and conducting studies of other patients will be helpful to learn more about this pathological mutation. In addition to the presentation of the case, we will discuss the existing forms of treatment.

Interferon-gamma signaling is downregulated in peripheral blood mononuclear cells from asthma patients / A sinalização de interferon-gama é diminuída em células mononucleares do sangue periférico de pacientes asmáticos

Introduction: Interferon-gamma (IFN-g) signaling is mediated by crosstalk of receptors, such as IFN-g receptor 1 (IFN-g R1), transcription factors, such as signal transducer and activator of transcription 1 (STAT1) and suppressors of cytokine signaling 1 (SOCS1). Here, we evaluated the role of IFN-g signaling in peripheral blood mononuclear cells (PBMCs) from asthma patients and control individuals. Methods: PBMCs from adult healthy nonasthmatic controls (n = 12; male and female, 18-60 years old) and patients diagnosed with asthma (n = 18; male and female, 18-60 years old) were stimulated with IFN-g (0.25, 0.5 and/or 1.0 ng/mL) and, after 24h, the production of CXC motif chemokine 10 (CXCL10) was evaluated (by enzyme linked immunosorbent assay) as well as the expression of IFN-g R1, STAT1 (both by flow cytometry assay) and SOCS1 (by real-time qPCR assay). Results: CXCL10 production was reduced in a dose-dependent manner in PBMCs from asthma patients stimulated with IFN-g when compared to control individuals. While IFN-g induced an increase in IFN-g R1 expression and phosphorylated STAT1 (pSTAT1) activation in PBMCs from the control group, a reduction in both IFN-g R1 and pSTAT1 was observed in PBMCs from asthma patients. IFN-g increased SOCS1 mRNA expression in PBMCs from asthma patients when compared to IFN-g-stimulated cells from control individuals. Conclusion: Taken together, our results demonstrated that IFN-g signaling is downregulated in asthma patients.

Introdução: A sinalização de interferon-gama (IFN-g) é mediada por receptores, como o receptor 1 de IFN-gama (IFN-gR1), fatores de transcrição, como o transdutor de sinal e o ativador de transcrição 1 (STAT1) e supressores de sinalização de citocina 1 (SOCS1). Neste trabalho, avaliamos o papel da sinalização de IFN-g em células mononucleares do sangue periférico (PBMCs) de indivíduos com asma e controle. Métodos: Células mononucleares do sangue periférico (PBMCs) de adultos saudáveis e não asmáticos (n = 12, homens e mulheres, 18-60 anos) e pacientes diagnosticados com asma (n = 18, homens e mulheres, 18-60 anos) foram estimuladas com IFN-g (0,25, 0,5 e/ou 1,0 ng/mL) e após 24 horas a produção de CXCL10 foi avaliada por ensaio de imunoabsorção enzimática (ELISA), bem como o receptor 1 de IFN-g (IFN-g R1). Também foram avaliadas as expressões do transdutor de sinal e ativador da transcrição 1 (STAT1) (por citometria de fluxo) e supressor de expressão de sinalização de citocinas 1 (SOCS1) (por ensaio qPCR em tempo real). Resultados: A produção de CXCL10, uma quimiocina induzida por IFNg, foi reduzida de maneira dependente da dose em PBMCs de pacientes com asma estimulados com IFN-g (0,25-1,0 ng/mL) quando comparado ao grupo controle. Enquanto IFN-g induziu um aumento da expressão de IFN-g R1 e ativação da fosforilação de STAT1 (pSTAT1) em PBMCs do grupo controle, uma redução de ambas (IFN-g R1 e pSTAT1) foi observada em PBMCs de pacientes com asma. O IFN-g aumentou as PBMCs de expressão do mRNA de SOCS1 de pacientes com asma quando comparado às células estimuladas por IFN-g do controle. Conclusão: Em conjunto, nossos resultados demonstraram que a sinalização de IFN-g é sub-regulada em pacientes com asma.

Role of signal transduction and transcription factors STAT1 and STAT3 in the pathogenesis of hepatocellular carcinoma and liver failure / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) and liver failure are common liver diseases in China and have extremely high incidence and mortality rates. Although there are many related studies, the detailed pathogenesis of these two diseases is still unknown. This article reviews the role of STAT1 and STAT3 phosphorylation proteins in the pathogenesis of HCC and liver failure, such as antiviral defense, acute phase response, liver injury, repair, inflammation, and transformation. A deep understanding of their role in the pathogenesis of HCC and liver failure and the development of related drugs with them as molecular targets play an important role in reducing mortality rate in clinical practice.

Bronchiectasis and Recurrent Respiratory Infections with a De Novo STAT1 Gain-of-Function Variant: First Case in Korea

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.

Role of STAT1 signaling pathway in osteoblast apoptosis and effect of blocking the path / 中国医师杂志

Objective To investigate the role of signal transducer and activator of transcription (STAT1) signaling pathway in osteoblast apoptosis,and to study the effect of STAT1 inhibitor (fludarabine) on osteoblast.Methods The viability of the osteoblasts in different concentration of fludarabine was detected by cell counting kit-8 (CCK-8) assay.Osteoblasts were divided into 4 groups:control group,dexamethasone (Dex) group,fludarabine (Flu) group,and Dex + Flu group.Enzyme linked immunosorbent (ELISA) was used for determining the protein expression of Bcl-2 Associated X Protein (BAX),STAT1 and phosphorylation-sigual transducers and activators of transcription 1 (p-STAT1),and cleaved caspase-3 to reflect the apoptosis in all groups.Results Treatment with Dex increased the protein expression of apoptosis-related proteins and p-STAT1 in time-dependent and dose-dependent manner.Exposure of the cells to Flu,which was a selective STAT1 inhibitor,resulted in a decreased the protein levels of apoptosis-related proteins.Conclusions Our results suggest that fludarabine could suppress Dex-induced apoptosis through the inhibition of STATl-mediated up-regulation cleaved caspase-3 expression in osteoblasts.

Effects of tacrolimus on the secretion of chemokines CXCL9 and CXCL10 by γ-interferon-simulated HaCaT cells / 中华皮肤科杂志

Objective To analyze effects of tacrolimus on the secretion of chemokines CXCL9 and CXCL10 by γ-interferon (IFN-γ)-simulated HaCaT cells,as well as phosphorylated Janus kinase 1 (p-JAK1) and phosphorylated signal transducer and activator of transcription 1 (p-STAT1),and to explore the mechanism of tacrolimus in the treatment of vitiligo.Methods HaCaT cells were treated with l,10,20,40,60,80,100,120 mg/L tacrolimus solution separately for 4 hours,and methyl thiazolyl tetrazolium (MTT) assay was performed to evaluate the cellular proliferative activity.HaCaT cells were divided into 4 groups:blank control group receiving no treatment,IFN-γgroup treated with 500 U/ml IFN-γfor 12 or 48 hours,tacrolimus group treated with 20 mg/L tacrolimus for 4 hours,and tacrolimus + IFN-γgroup treated with 20 mg/L tacrolimus for 4 hours followed by the treatment with 500 U/ml IFN-γfor 12 or 48 hours.Real-time fluorescence-based quantitative PCR was conducted to measure the mRNA expression of CXCL9 and CXCL10,Western blot analysis to determine the protein expression of CXCL9,CXCL10,p-JAK1,and p-STAT1,and enzyme-linked immunosorbent assay (ELISA) to detect the levels of CXCL9 and CXCL10 in the culture supernatants of HaCaT cells.Results Tacrolimus at the maximum concentration of 20 mg/L had no effect on the proliferation of HaCaT cells (P ＞ 0.05).After the pretreatment with 20 mg/L tacrolimus,the mRNA expression of CXCL9 and CXCL10 significantly decreased from 10 369.08 ± 7.99 and 290.02 ± 2.16 to 5 914.33 ± 4.59 and 114.96 ± 0.73,respectively,after the treatment with IFN-γ(both P ＜ 0.01),and the protein expression of CXCL9,CXCL10,p-JAK1,and p-STAT1 also significantly decreased from 8.47 ± 0.29,7.87 ± 0.17,4.20 ± 0.18 and 4.29 ± 0.11 to 7.36 ± 0.13,7.36 ± 0.09,2.60 ± 0.16 and 3.62 ± 0.19,respectively,after the treatment with IFN-γ (all P ＜ 0.01).Moreover,the levels of CXCL9 and CXCL10 in the culture supernatants of HaCaT cells significantly decreased in the IFN-γgroup (1 213.36 ± 0.95,1 722.41 ± 2.57,respectively) compared with the tacrolimus + IFN-γ group (426.45 ± 0.31,554.12 ± 0.56,respectively,both P ＜ 0.01).Conclusion Tacrolimus can inhibit the secretion of CXCL9,CXCL10,p-JAK1 and p-STAT1 by HaCaT cells stimulated by IFN-γ.

Effect of danshensu on expression of STAT1, PPARγ and hepatocyte growth factor in the liver of mice with streptozotocin-induced diabetes / 第二军医大学学报

Objective To study the effect of Danshensu on the expressions of signal transducer and activator of transcription 1 (STAT1), pero xiome proliferators-activated receptor-γ (PPAR-γ) and hepatocyte growth factor (HGF) in streptozotocin-induced diabetic mice, and to assess its protective effect on the liver of mice. Methods Diabetic mice were induced by intraperitoneal injection of 500 mg streptozotocin (200 mg/kg). Then the diabetic mice were randomly divided into four groups: diabetic model group, low-dose Danshensu (15 mg/kg) group, middle-dose Danshensu (30 mg/kg) group and high-dose Danshensu (60 mg/kg) group, with 10 mice in each group. Danshensu (sodium salt of Danshensu) was administered intragastrically once a day for 12 weeks. Ten normal mice were taken as controls. The fasting blood glucose, insulin and glycosylated hemoglobin (GHb) levels were examined at 12 h after the last administration of the drug. The aspartate transaminade(AST) and alanine transaminade (ALT) levels in sera drawn from inner canthus were determined by automatic biochemical analyser. Western blotting analysis was used to examine the expression of STAT1, PPARγ and HGF in the liver tissues. Results (1) Compared with control group, the diabetic model group and Danshensu groups had significantly higher blood glucose and GHb levels (P<0. 01) and significantly lower insulin level (P<0. 01). There were no significant differences between the three Danshensu groups concerning the three parameters. (2) The levels of AST and ALT in diabetic model group were significantly higher than those in the control group (P<0.05); their levels in the three Danshensu groups were significantly lower than those of the diabetic model group (P<0.05); there were no significant differences among the three Danshensu groups. (3) The expression of STAT1 in diabetic model group was significantly higher and the expression of PPARy and HGF was significantly lower than those in control group (P<0.01). Compared with the diabetic model group, PPARγ and HGF expression in the liver tissues was significantly increased and STAT1 expression was significantly decreased in a dose-dependent manner with Danshensu (P < 0.01). Conclusion The protective effect of Danshensu on liver tissues in streptozotocin-induced diabetic mice might be associated with increase of PPARy and HGF expression and decrease of STAT1 expression.

Signal transducer and activator of transcription 1 and matrix metalloproteinase 3's genetic expression and their clinical significance on urothelial tumor after renal transplantation / 中华泌尿外科杂志

Objective To investigate the signal transducer and activator of transcription 1(STAT1) and matrix metalloproteinase 3(MMP3)′s genetic expressions and their clinical significance on urothelial carcinoma after renal transplantation. Methods Fifty-one patients with urothelial carcinoma were recruited in this study. Sixteen of them who had renal transplant were in the experimental group and 35 of them without renal transplant were in the control group. All the cases had been proved postoperatively having transitional cell carcinoma by histopathological study. The human genome oligo arrays were used to analyze the gene expression spectrum of urothelial carcinoma after transplantation, aiming the STAT1 and MMP3's expression. Real time RT-PCR and immunohistochemical staining were used to compare the differences in the 2 groups. Results The experimental group showed that there were 35 genes up-regulated compared with the control group. Of them, 23had known gene function or partly known, and 12 had unknown gene function. There were 76 genes down-regulated. Of them, 46 had known gene function or partly known, and 30 had unknown gene function. After pathway analysis of the differentially expressed genes, there were 23 groups of pathways which had significant differences (P＜0.05), referring to the aspects of immunosuppressive and tumor growth. The levels of STAT1 and MMP3 expressions had significant differences between the 2groups(P＜0.05)as well. Conclusions The differential expression of urothelial tumor genes is obvious between patient who has had renal transplant and who has not. There are many aspects that are related to the tumor's growth like signaling pathways regulating proliferation, apoptosis of tumor cells, tumor angiogenesis and the tumor metastasis potential. STAT1 and MMP3 maybe become the targets of chemoprevention for post-transplantation urothelial carcinoma.