背景：最近6年定义了两种受体相互作用丝氨酸/苏氨酸蛋白激酶1（receptor-interacting serine/threonine-protein kinase 1，RIPK1）相关免疫出生错误（inborn errors of immunity，IEI），即RIPK1功能获得性突变引起的自身炎症伴阵发性发热和淋巴结肿大（autoinflammation with episodic fever and lymphadenopathy, AIEFL），以及RIPK1双等位基因功能丧失性突变引起的免疫缺陷57型伴自身炎症（immunodeficiency 57 with autoinflammation）（RIPK1缺陷症）。本研究纳入了3例携带RIPK1罕见变异的患者，均主要表现为不明原因发热，诊断自身炎症性疾病。方法：收集携带RIPK1罕见变异的自身炎症性疾病患者临床资料，对AIEFL和RIPK1缺陷症的患者进行文献复习。对发现的RIPK1基因4个罕见变异进行检索，确定其是否收录在数据库中，确定其ACMG致病分级。使用蛋白三维结构预测和多序列比对分析预测变异致病性。结果：3例携带RIPK1杂合变异的自身炎症性疾病患者均表现为不明原因周期性发热，分别携带杂合RIPK1 V646E，A404S和Y128*突变。携带V646E和A404S的患者出现典型的自身炎症性疾病特征，Y128*患者除自身炎症性疾病特征之外还表现出轻度免疫缺陷。文献复习显示AIEFL主要表现为不明原因发热以及淋巴结肿大，突变位点位于321或者324位点，而RIPK1缺陷症则表现为严重的免疫缺陷及早发性炎性肠病，突变主要位于激酶结构域和死亡结构域。蛋白三维结构预测显示A404S变异比野生型多出两个氢键，404位点在222种哺乳动物中的182种保守，646位点则在其中的219种中保守。这些结果表明这两个位点都有很高的保守性，具有致病可能。本研究还发现2例同时携带RIPK1 D132N杂合变异以及其他单基因自身炎症疾病相关基因变异的患者。结论：Y128*和V646E的杂合RIPK1变异可能表现出功能丧失，可能是一种新的RIPK1相关IEI，即RIPK1单倍体剂量不足。RIPK1 D132N的功能仍需探索，该变异与其他单基因自身炎症疾病相关基因良性变异的共现可能与自身炎症性疾病有关。

Background

In recent years, two forms of receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-related inborn errors of immunity (IEI) have been characterized: autoinflammation with episodic fever and lymphadenopathy (AIEFL), which is caused by gain-of-function mutation in RIPK1, and immunodeficiency 57 with autoinflammation, which results from biallelic loss-of-function mutations in RIPK1 (termed "RIPK1 deficiency"). Our study has encountered three patients carrying rare RIPK1 variants, all of whom presented primarily with unexplained fever and a clear diagnosis of autoinflammatory disease.

Methods

We collected clinical data of patients carrying rare RIPK1 variants. Literature on patients previously reported with AIEFL and RIPK1 deficiency was also reviewed. Four rare variants were investigated for inclusion in databases and their pathogenicity classification according to ACMG guidelines. Protein structure prediction and multiple sequence alignment were used to predict the pathogenic potential of the variants.

Results

Three patients all presented with recurrent unexplained fever as their chief complaint and were found to carry the heterozygous RIPK1 variants V646E, A404S, and Y128*. Patients with V646E and A404S variants showed typical autoinflammatory features, while Y128* variant was associated with mild immunodeficiency beyond the inflammatory features. Literature review indicated that AIEFL typically presents with unexplained fever and lymphadenopathy, with mutations located at positions 321 or 324, whereas RIPK1 deficiency presents with severe immunodeficiency and early-onset inflammatory bowel disease features, with mutations primarily in the kinase and death domains. Protein structure prediction showed that the A404S variant introduces two additional hydrogen bonds compared to the wild type, and position 404 is conserved in 182 out of 222 mammalian species surveyed, while position 646 is conserved in 219 species. These findings suggest a high conservation of these sites, implying a potential for pathogenicity. This study also identified two patients carrying other monogenic autoinflammatory disease variants along with RIPK1 D132N variant.

Conclusion

RIPK1 Y128* and V646E variant may represent a loss of function, potentially defining a new form of RIPK1-related IEI. The function of RIPK1 D132N needs further exploration, and its co-occurrence with other benign variants may be associated with autoinflammation.