Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis
Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis
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DOI：
10.1093/rheumatology/kep418
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发表时间：
2010-03-01
期刊：
影响因子：
5.5
通讯作者：
Kuis, Wietse
中科院分区：
文献类型：
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作者：
Vastert, Sebastiaan J.;van Wijk, Richard;Kuis, Wietse
Objective.巨噬细胞活化综合征（MAS）是幼年特发性关节炎（SoJIA）的一种获得性家族性噬血细胞性淋巴组织细胞增生症（fHLH）。FHLH是一种常染色体隐性遗传疾病，其特征是NK细胞功能下降，20-50%的患者由穿孔素基因（PRF 1）突变引起。有趣的是，SoJIA患者显示NK细胞中穿孔素水平降低，NK细胞功能也降低。在这里，我们分析了PRF 1及其假定的启动子在SoJIA患者或没有MAS的历史。分离了56名SoJIA患者（41名意大利人和15名荷兰人）的DNA。其中15例（27%）有经证实的MAS病史。我们对PRF 1和1.5kb的5 '上游区域进行了测序。在使用人NK细胞系的转染实验中，对启动子区的DNA序列变异进行了功能性测试。我们在18%的SoJIA患者的PRF 1启动子中检测到一个以前未描述的序列变异（-499 C > T）。然而，转染实验并没有显示这种变化的功能影响。其次，我们发现56例SoJIA患者中有11例（20%）为PRF 1错义突变杂合子。特别是，我们发现了一个高患病率的Ala 91 Val突变，已知导致穿孔素功能缺陷的变体。有趣的是，Ala 91 Val在有MAS病史的SoJIA患者中的患病率（20%）与没有MAS的SoJIA患者（9.8%）相比有所增加。1例Ala 91 Val杂合子SoJIA患者在MAS时表现出穿孔素水平显著降低。这些发现表明PRF 1突变在SoJIA患者MAS的发展中起作用。
Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.Methods. DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5'-upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line.Results. We detected a previously undescribed sequence variation (-499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS.Conclusions. These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients.