A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal-dominant recurrent fever.
A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal-dominant recurrent fever.
复制标题
常染色体显性反复发热芬兰家族中肿瘤坏死因子受体 1 第三胞外结构域的新突变。
作者：
H. Nevala;L. Karenko;S. Stjernberg;M. Raatikainen;H. Suomalainen;A. Lagerstedt;Jenita Rauta;M. McDermott;P. Peterson;T. Pettersson;A. Ranki
客观化
目的探讨肿瘤坏死因子受体超家族基因(TNFRSF1A，CD120a)突变引起的肿瘤坏死因子受体相关周期综合征(TRAPS)在一个复发性发热芬兰家系中的存在。
方法
对患病和未发病的家系成员进行了TNFRSF1A基因测序。流式细胞术和酶联免疫吸附分析分别检测细胞膜表达和血清中TNFRSF1A蛋白的水平。
结果
在4个家系成员和1名无症状个体中均发现了位于TNFRSF1A胞外区第三外显子的错义突变，导致氨基酸替换(F112I)，接近保守的半胱氨酸。该突变明显与低水平的可溶性TNFRSF1A以及反复发烧和腹痛的临床症状有关。携带该突变的3名成年家系成员的外周血粒细胞和单核细胞中均检测到佛波酯刺激后TNFRSF1a的脱落受损，但在携带该突变且有新发临床症状的儿童中，该突变的脱落缺陷不明显。
结论
任何有间歇性发热史并伴有不明原因的腹痛、关节炎或皮疹的患者，尤其是有此类症状的家族史的患者，应怀疑陷阱。对血清中低水平的可溶性TNFRSF1A进行筛查，以确定可能存在TNFRSF1A突变的个体。
OBJECTIVE
To investigate the presence of TRAPS (tumor necrosis factor receptor-associated periodic syndrome), which is a recently defined, dominantly inherited autoinflammatory syndrome caused by mutations in the tumor necrosis factor receptor superfamily 1A gene (TNFRSF1A, CD120a), in a Finnish family with recurrent fever.
METHODS
The TNFRSF1A gene was sequenced in both affected and unaffected family members. Flow cytometry and enzyme-linked immunosorbent assay analyses were used to assess membrane expression and serum levels of the TNFRSF1A protein, respectively.
RESULTS
A missense mutation in exon 4, located in the third extracellular domain of TNFRSF1A and resulting in an amino acid substitution (F112I) close to a conserved cysteine, was found in all 4 affected family members and in 1 asymptomatic individual. The mutation was clearly associated with low levels of soluble TNFRSF1A as well as with the clinical symptoms of recurrent fever and abdominal pain. Impaired shedding of TNFRSF1A after phorbol myristate acetate stimulation was detected in blood granulocytes and monocytes from the 3 adult family members with the mutation, but in the child bearing the mutation and showing clinical symptoms of recent onset, the shedding defect was less marked.
CONCLUSION
TRAPS should be suspected in any patient who presents with a history of intermittent fever accompanied by unexplained abdominal pain, arthritis, or skin rash, particularly in the presence of a family history of such symptoms. Screening for low serum levels of soluble TNFRSF1A identifies individuals who are likely to have TNFRSF1A mutations.