The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.
The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.
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DOI：
10.1007/s10875-015-0214-9
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发表时间：
2016-01
影响因子：
9.1
通讯作者：
Grimbacher B
中科院分区：
文献类型：
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作者：
Depner M;Fuchs S;Raabe J;Frede N;Glocker C;Doffinger R;Gkrania-Klotsas E;Kumararatne D;Atkinson TP;Schroeder HW Jr;Niehues T;Dückers G;Stray-Pedersen A;Baumann U;Schmidt R;Franco JL;Orrego J;Ben-Shoshan M;McCusker C;Jacob CM;Carneiro-Sampaio M;Devlin LA;Edgar JD;Henderson P;Russell RK;Skytte AB;Seneviratne SL;Wanders J;Stauss H;Meyts I;Moens L;Jesenak M;Kobbe R;Borte S;Borte M;Wright DA;Hagin D;Torgerson TR;Grimbacher B
信号转导和转录激活因子1 （STAT1）的功能获得（GOF）突变导致STAT信号不平衡，导致免疫失调和免疫缺陷。后者通常以易复发念珠菌感染为特征，导致慢性皮肤粘膜念珠菌病（CMC）的临床表现。本研究旨在评估大型国际CMC患者队列中GOF STAT1突变的频率。对57例CMC患者和35名健康家庭成员的基因组DNA进行STAT1测序。通过流式细胞术分析干扰素(IFN)-α、IFN-γ或白细胞介素-27刺激后患者外周血细胞（PBMC）中STAT1磷酸化水平，显示了9种不同STAT1变异的功能相关性。收集并总结了26例患者的扩展临床数据集。57例CMC患者中有35例（61%）存在STAT1杂合突变。在来自11个家族的39例家族性病例中，来自9个家族的26例患者（67%），以及18例散发病例中，9例患者（50%）在STAT1中存在杂合突变。本文报道了13种不同的STAT1突变。这些突变中有8个已知会导致CMC （p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D和p.F404Y）。然而，5种STAT1变异（p.F172L、p.p y287d、p.P293S、p.T385K和p.S466R）在CMC患者中未见报道。在CMC患者中经常观察到STAT1突变。因此，建议对CMC患者进行STAT1序列分析。测量IFN或il诱导的PBMC中STAT1磷酸化提供了一种快速可靠的诊断工具，应该在基因检测之外进行。
Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients’ peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.