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首页> 美国卫生研究院文献>American Journal of Human Genetics >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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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

机译：肿瘤坏死因子受体相关的周期性综合征：TNFRSF1A的新突变祖先的起源基因型-表型研究和周期性发热的进一步遗传异质性的证据。

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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 ∼1% 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.
机译：55-kD肿瘤坏死因子（TNF）受体（TNFRSF1A）是炎症的关键调节剂，其胞外域突变定义为周期性发热综合征TRAPS（TNF受体相关周期性综合征[MIM 142680]），其特征是发烧，无菌性腹膜炎，关节痛，肌痛，皮疹和/或结膜炎发作。一些患者还发展为全身性淀粉样变性。在其他地方，我们描述了六个与疾病相关的TNFRSF1A突变，其中五个破坏了参与二硫键的细胞外半胱氨酸。随后报道了另外四个突变。在另外150名原因不明的周期性发烧患者中，我们确定了四个新的TNFRSF1A突变（H22Y，C33G，S86P和c.193-14 G→A），一个由另一组描述的突变（C30S）和两个取代（P46L和R92Q）存在于约1％的对照染色体中。定期发烧患者中P46L和R92Q的频率增加以及TNFRSF1A的功能研究认为，这些是低渗透性突变，而不是良性多态性。 c.193-14 G→A突变在外显子3的上游产生一个剪接受体位点，从而产生了一个编码四个其他胞外氨基酸的转录本。 T50M和c.193-14 G→A发生在CpG热点，单倍型分析与这些位点的反复突变是一致的。相比之下，尽管R92Q也出现在CpG基序上，但我们在不相关的个​​体中发现了具有此替换的共同创始染色体。基因型-表型研究确定了14例TRAPS和淀粉样变性患者中的13例为半胱氨酸突变的携带者，并指出非半胱氨酸突变个体中TRAPS症状的渗透率较低。尽管有两个外显子的全面基因组测序，但在两个具有显性遗传性疾病的家族中，以及在90个散发病例中都有可兼容的临床病史，我们尚未发现任何TNFRSF1A突变，因此提示了周期性发热综合征的进一步遗传异质性。

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