Ida H, Kawasaki E, Miyashita T, Tanaka F, Kamachi M, Izumi Y, Huang M, Tamai M, Origuchi T, Kawakami A, Migita K, Motomura M, Yoshimura T, Eguchi K
First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Rheumatology (Oxford). 2004 Oct;43(10):1292-9. doi: 10.1093/rheumatology/keh320. Epub 2004 Jul 27.
To identify potential mutations in the tumour necrosis factor receptor superfamily 1A gene (TNFRSF1A) in a Japanese female patient with recurrent fever complicated by systemic lupus erythematosus (SLE), and in her family members.
DNA sequencing of exons 1-10 of the TNFRSF1A gene was performed to determine mutations that might be associated with the tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Moreover, the TNFRSF1A gene was examined in Japanese patients with autoimmune diseases, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD) and Behçet's disease, and in healthy Japanese controls. Enzyme-amplified sensitivity immunoassay (EASIA) analysis was used to assess serum levels of TNF, the 55-kDa TNF receptor (TNFRSF1A) and the 75-kDa TNF receptor (TNFRSF1B). Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry.
A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient. Two nieces and one nephew, all with a similar clinical phenotype, also possessed the same TNFRSF1A mutation. We further demonstrated the same mutation in five of 60 SLE patients (8.3%) and in five of 120 healthy individuals (4.2%), with no significant differences. Although high titres of serum TNF and soluble TNFRSF1B protein were observed in this patient, low titres of soluble TNFRSF1A protein were detected. However, a defect in TNFRSF1A shedding in vitro was not observed in monocytes derived from this patient.
This is the first report of a TRAPS patient associated with SLE with a novel TNFRSF1A mutation (T61I).
在一名患有复发性发热并伴有系统性红斑狼疮（SLE）的日本女性患者及其家庭成员中，鉴定肿瘤坏死因子受体超家族1A基因（TNFRSF1A）中的潜在突变。
对TNFRSF1A基因的第1至10外显子进行DNA测序，以确定可能与肿瘤坏死因子受体相关的周期性综合征（TRAPS）相关的突变。此外，对包括SLE、类风湿关节炎（RA）、混合性结缔组织病（MCTD）和白塞病在内的日本自身免疫性疾病患者以及健康的日本对照者进行TNFRSF1A基因检测。采用酶放大敏感性免疫分析（EASIA）来评估血清中肿瘤坏死因子（TNF）、55 kDa肿瘤坏死因子受体（TNFRSF1A）和75 kDa肿瘤坏死因子受体（TNFRSF1B）的水平。通过流式细胞术分析外周血单核细胞表面的膜TNFRSF1A表达。
在一名日本女性TRAPS患者的基因组DNA衍生的TNFRSF1A基因中检测到一个新的突变，即第3外显子中杂合的C到T转换，该转换在第61位将苏氨酸替换为异亮氨酸（T61I）。两名侄女和一名侄子，均具有相似的临床表型，也携带相同的TNFRSF1A突变。我们进一步在60例SLE患者中的5例（8.3%）和120名健康个体中的5例（4.2%）中证实了相同的突变，差异无统计学意义。尽管在该患者中观察到血清TNF和可溶性TNFRSF1B蛋白的高滴度，但检测到可溶性TNFRSF1A蛋白的低滴度。然而，在该患者来源的单核细胞中未观察到体外TNFRSF1A脱落缺陷。
这是首例与SLE相关的伴有新型TNFRSF1A突变（T61I）的TRAPS患者的报告。
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