The TNF receptor-associate periodic syndrome (TRAPS) - Emerging concepts of an autoinflammatory disorder
The TNF receptor-associate periodic syndrome (TRAPS) - Emerging concepts of an autoinflammatory disorder
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DOI：
10.1097/00005792-200209000-00002
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发表时间：
2002-09-01
期刊：
影响因子：
1.6
通讯作者：
Kastner, DL
中科院分区：
文献类型：
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作者：
Hull, KM;Drewe, E;Kastner, DL
本报告描述并扩展了自身炎症性疾病肿瘤坏死因子（TNF）受体相关周期性综合征（TRAPS）的临床和遗传谱。自1999年首次发现TNF受体超家族1A （TNFRSF1A）中的6个错义突变以来，共鉴定了20个突变。其中18个突变导致受体细胞外部分的前2个富含半胱氨酸结构域（CRDs）内的氨基酸替换。单剪接突变也通过引起4个氨基酸的插入影响第一个CRD。对最常见的异种突变R92Q的单倍型分析表明，它有一个古老的创始人；然而，对爱尔兰和苏格兰家庭中另一种常见突变T50M突变的分析却没有发现，这表明T50M是一种反复发生的突变。导致半胱氨酸替代的突变显示出更高的临床表型外显率（93%对82%的非半胱氨酸残基替代），并且还增加了发生危及生命的淀粉样变性的可能性（24%对2%的非半胱氨酸残基替代）。对50多名患者的回顾性和前瞻性评估，代表了20个已知突变中的10个，使我们能够扩展和更好地定义TRAPS的临床谱。反复发作的发热、肌痛、皮疹、腹痛和结膜炎通常持续5天以上是TRAPS最典型的临床特征。TNFRSF1A的缺陷脱落只能部分解释TRAPS的病理生理机制，因为一些突变具有正常的脱落。因此，其他机制可能介导观察到的表型。我们目前正在研究其他可能的机制，在体外使用稳定和瞬时转染的细胞系统，以及开发敲入小鼠模型。初步数据表明依那西普可能对降低trap患者的严重程度、持续时间和症状频率有效。此外，它提供了一种可行的治疗替代糖皮质激素治疗，糖皮质激素治疗有许多严重的，长期的副作用。目前正在进行两项临床试验，以评估依那西普在降低trap症状发生频率和严重程度方面的疗效。最后，我们总结了R92Q和P46L，以及可能尚未发现的替换，代表非常低的外显率突变，可能在更广泛定义的炎症性疾病（如类风湿关节炎）中发挥更大的作用。我们的实验室目前正在进行临床和基础研究，以确定这些突变在更常见的炎症性疾病中的作用。
The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions).Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS.Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model.Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS.Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.