The tumor-necrosis-factor receptor-associated periodic syndrome:: New mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers
The tumor-necrosis-factor receptor-associated periodic syndrome:: New mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers
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DOI：
10.1086/321976
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发表时间：
2001-08-01
影响因子：
9.8
通讯作者：
Kastner, DL
中科院分区：
文献类型：
--
作者：
Aksentijevich, I;Galon, J;Kastner, DL
55-kD肿瘤坏死因子（TNF）受体（TNFRSF 1A）（炎症的关键调节因子）胞外结构域的突变定义了一种发热综合征，TRAPS（TNF受体相关周期性综合征[MIM 142680]），其特征为发热、无菌性腹膜炎、关节痛、肌痛、皮疹和/或结膜炎发作;一些患者还发生系统性淀粉样变性。在其他地方，我们已经描述了六个疾病相关的TNFRSF 1A突变，其中五个破坏参与二硫键的细胞外半胱氨酸;其他四个突变随后被报道。在另外150例不明原因的周期性发热患者中，我们发现了四种新的TNFRSF 1A突变（H22 Y，C33 G，S86 P和c。193-14 G-->A），另一组描述了一个突变（C30 S），以及两个替换（P46 L和R92 Q），在对照染色体中的存在率接近1%。周期性发热患者中P46 L和R92 Q频率的增加，以及TNFRSF 1A的功能研究，认为这些是低突变率突变而不是良性多态性。梭193-14 G-->A突变在外显子3上游产生一个剪接受体位点，产生一个编码四个额外胞外氨基酸的转录本。T50 M和C. 193-14 G-->A发生在CpG热点，单倍型分析与这些位点的复发突变一致。相比之下，虽然R92 Q也出现在CpG基序，我们确定了一个共同的创始人染色体在不相关的个人与此取代。基因型-表型研究发现，14例TRAPS和淀粉样变性患者中有13例为半胱氨酸突变携带者，并表明非半胱氨酸突变个体的TRAPS症状发生率较低。在两个显性遗传性疾病家族和90例具有相容临床病史的散发病例中，尽管对所有外显子进行了全面的基因组测序，但我们尚未发现任何TNFRSF 1A突变，因此提示了黄热病综合征的进一步遗传异质性。
Mutations in the extracellular domain of the 55-kD tumor-necrosis factor (TNF) receptor (TNFRSF1A), a key regulator of inflammation, define a periodic-fever syndrome, TRAPS (TNF receptor-associated periodic syndrome [MIM 142680]), which is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and/or conjunctivitis; some patients also develop systemic amyloidosis. Elsewhere we have described six disease-associated TNFRSF1A mutations, five of which disrupt extracellular cysteines involved in disulfide bonds; four other mutations have subsequently been reported. Among 150 additional patients with unexplained periodic fevers, we have identified four novel TNFRSF1A mutations (H22Y, C33G, S86P, and c. 193-14 G-->A), one mutation (C30S) described by another group, and two substitutions (P46L and R92Q) present in similar to1% of control chromosomes. The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, argue that these are low- penetrance mutations rather than benign polymorphisms. The c. 193-14 G-->A mutation creates a splice-acceptor site upstream of exon 3, resulting in a transcript encoding four additional extracellular amino acids. T50M and c. 193-14 G-->A occur at CpG hotspots, and haplotype analysis is consistent with recurrent mutations at these sites. In contrast, although R92Q also arises at a CpG motif, we identified a common founder chromosome in unrelated individuals with this substitution. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TRAPS and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations. In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes.