Two Adult Siblings With Atypical Cryopyrin-Associated Periodic Syndrome Due to a Novel M299V Mutation in NLRP3
Two Adult Siblings With Atypical Cryopyrin-Associated Periodic Syndrome Due to a Novel M299V Mutation in NLRP3
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DOI：
10.1002/art.27489
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发表时间：
2010-07-01
影响因子：
--
通讯作者：
Soderkvist, Peter
中科院分区：
文献类型：
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作者：
Verma, Deepti;Eriksson, Per;Soderkvist, Peter
目标。NALP3炎性小体是一种多蛋白复合物，可触发caspase 1介导的白细胞介素-1 β (IL-1 β)释放。编码NALP3 （NLRP3）的基因突变是低温素相关周期综合征（CAPS）的基础。本研究的目的是报道一种新的NLRP3突变，发生在两名瑞典血统的兄弟姐妹中，他们在成年后首次出现症状。对cap患者和100名对照者的DNA进行NLRP3突变分析。为了评估caspase 1和IL-1 β，收集了患者和年龄和性别匹配的健康对照者的血液。将含有突变型或野生型NLRP3的遗传构建物导入THP-1细胞，然后评估细胞上清中IL-1 β的水平。兄妹俩都携带NLRP3的M299V突变，这在对照人群中不存在。从患者身上获得的样本显示，在基础条件下，与健康对照组相比，caspase 1活性增加，IL-1 β水平升高。表达突变M299V的THP-1细胞的IL-1 β产量比野生型高近10倍。M299V是NLRP3的一个激活突变，导致自发性caspase 1活性和IL-1 β水平升高。这些成年兄弟姐妹缺乏典型的CAPS表型。其中一个兄弟姐妹表现出较轻的表型，迄今为止对口服非甾体类抗炎药物联合低剂量皮质类固醇有满意的反应，而另一个更严重的兄弟姐妹的炎症症状对IL-1 β阻断反应良好。了解这些疾病的致病机制对医生是有帮助的。我们的研究强调了基因检测和实验室调查结合仔细的表型评估对此类患者诊断的重要性。
Objective. The NALP3 inflammasome is a multiprotein complex that triggers caspase 1-mediated interleukin-1 beta (IL-1 beta) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood.Methods. Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1 beta, blood was collected from patients and age-and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1 beta levels in cell supernatant.Results. Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1 beta levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1 beta production compared with the wild-type construct.Conclusion. M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1 beta levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1 beta blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.