STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis
STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis
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DOI：
10.1056/nejmoa1100102
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发表时间：
2011-07-07
影响因子：
158.5
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
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作者：
van de Veerdonk, Frank L.;Plantinga, Theo S.;Netea, Mihai G.
慢性黏膜皮肤念珠菌病(CMC)的特征是皮肤、指甲和粘膜对念珠菌感染的易感性。隐性CMC和自身免疫病患者自身免疫调节因子AIRE发生突变。方法对来自5个常染色体显性遗传CMC家系的14例患者进行分析。我们用不同的刺激物组合培养他们的外周血单核细胞，以测试调节免疫的途径的完整性，这导致选择了100个最有可能包含遗传缺陷的基因。我们使用基于阵列的序列捕获试验，随后的下一代测序来鉴定突变。结果患者的单个核细胞具有干扰素-γ、白介素17和白介素22产生不足的特征，提示缺陷存在于白介素12受体和白介素23受体的信号通路中。我们在患者中发现了编码信号转导和转录激活因子1(STAT1)的卷曲线圈(CC)结构域的DNA序列中的杂合性错义突变。这些突变导致1型和17型辅助T细胞(Th1和Th17)的反应缺陷。结论STAT1基因CC区突变是常染色体显性遗传CMC的基础，导致Th1和Th17应答缺陷，这可能是其对真菌感染易感性增加的原因。
BackgroundChronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown.MethodsWe evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations.ResultsThe mononuclear cells from the affected patients were characterized by poor production of interferon-gamma, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-gamma receptor pathway was intact in these patients.ConclusionsMutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection.