Tumor necrosis factor receptor-associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor:: implications for pathogenesis
Tumor necrosis factor receptor-associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor:: implications for pathogenesis
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DOI：
10.1002/art.11169
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发表时间：
2003-08-01
影响因子：
--
通讯作者：
Lorenz, HM
中科院分区：
文献类型：
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作者：
Kriegel, MA;Hüffmeier, U;Lorenz, HM
肿瘤坏死因子受体 (TNFR) 相关周期性综合征 (TRAPS；MIM 编号 142680) 是一种潜在致命的、常染色体显性遗传的自身炎症综合征，其特征是反复发作发烧、皮肤损伤以及腹部、关节或肌肉疼痛 (1-3)。迄今为止，已报道 TRAPS 患者的 TNFR 超家族 1A (TNFRSF1A) 膜远端域有 20 种突变 (4-6)。体外实验已证实脱落缺陷和血清水平降低 (1, 5)。据推测，一些突变会间接干扰激活诱导的裂解 (1, 5)，尽管这一过程发生在靠近跨膜区域的 Asn201–Val202 (7)。 TNFR1 脱落的氨肽酶调节剂 (ARTS-1) 与同一区域的受体结合并促进裂解 (8)。在此，我们描述了一个患有显性遗传性反复发热和关节炎的德国家庭中的一种新的 TNFRSF1A 突变 (I199N)。预计这种氨基酸取代会导致 TNFRSF1A 的裂解位点内形成氢键。我们还证明这种突变会导致受体脱落缺陷。所有接受测试的参与者均表示知情同意。指标患者（病例 III-2，图 1A）是一名 36 岁的德国南部女性，患有反复发作（大约每月到每季度一次）的发烧、咽炎、关节炎/关节痛和腰痛。第一次发作是在她 19 岁时；没有明显的触发因素。发作通常在晚上开始，接近午夜时强度最大，通常持续数天，有时超过一周。值得注意的是，在怀孕和哺乳期间，这些发作消失了。症状与急性期反应物水平的相关性如表 1 所示。指标患者（病例 II-2）的 66 岁母亲报告了几乎相同的病史，包括在傍晚时发作的最大强度以及在怀孕和哺乳期间没有发作。她的病是在20岁时发病的。绝经后，发作变得较轻，仅伴有咽炎和发烧，并且真正呈周期性（每 4 周一次）。据报道，外祖父（病例 I-1）患有不明原因的反复发烧。指示患者的孩子（病例 IV-1，6 岁和病例 IV-2，3 岁）迄今为止都很健康。尚未进行 DNA 测试。指标患者（病例 III-1）未受影响的 42 岁兄弟从未经历过周期性发烧，其他方面都很健康。
Tumor necrosis factor receptor (TNFR)–associated periodic syndrome (TRAPS; MIM no. 142680) is a potentially lethal, autosomal-dominantly inherited autoinflammatory syndrome characterized by recurrent attacks of fever, skin lesions, and abdominal, joint, or muscle pain (1–3). To date 20 mutations in the membrane-distal domains of TNFR superfamily 1A (TNFRSF1A) in patients with TRAPS have been reported (4–6). Defective shedding and reduced serum levels have been demonstrated in vitro (1, 5). It has been hypothesized that some mutations would indirectly interfere with activation-induced cleavage (1, 5), although this process occurs at Asn201–Val202 close to the transmembrane region (7). The aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the receptor at the same region and facilitates cleavage (8). Herein we describe a novel TNFRSF1A mutation (I199N) in a German family with dominantly inherited recurrent fever and arthritis. This amino acid substitution is predicted to cause hydrogen bond formation within the cleavage site of TNFRSF1A. We also demonstrate that this mutation causes defective shedding of the receptor. All participants tested gave their informed consent. The index patient (case III-2, Figure 1A) is a 36-year-old woman of southern German extraction with recurrent (occurring roughly monthly to quarterly) attacks of fever, pharyngitis, arthritis/arthralgia, and low back pain. The first attack was noted when she was 19 years old; there were no obvious triggers. Episodes usually started in the evening with a maximum intensity close to midnight and often lasted several days, sometimes more than a week. Remarkably, during pregnancy and breast-feeding, the attacks vanished. Correlations of the symptoms with levels of acute-phase reactants are shown in Table 1. The 66-year-old mother of the index patient (case II-2) reported an almost identical history, including maximum intensity of attacks in the late evening and lack of episodes during pregnancy and lactation. Onset of her disease was at 20 years of age. After menopause the attacks became milder with pharyngitis and fever only, and truly periodic (every 4 weeks). The maternal grandfather (case I-1) was reported to have had recurrent fever of unknown etiology. The children of the index patient (case IV-1, 6 years old and case IV-2, 3 years old) are healthy to date. No DNA tests have been performed. The unaffected 42-year-old brother of the index patient (case III-1) never experienced periodic fever attacks and is otherwise healthy.