JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency
JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency
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DOI：
10.1056/nejmoa1905633
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发表时间：
2020-01-16
影响因子：
158.5
通讯作者：
Alangari, Abdullah A.
中科院分区：
文献类型：
--
作者：
Alsohime, Fahad;Martin-Fernandez, Marta;Alangari, Abdullah A.
泛素特异性肽酶18（USP 18）缺乏是一种严重的I型干扰素病。USP 18通过阻断Janus相关激酶1（JAK1）进入I型干扰素受体下调I型干扰素信号传导。缺乏USP18导致未减轻的干扰素介导的炎症，并且在围产期期间是致命的。我们描述一个新生儿谁提出与脑积水，坏死性蜂窝织炎，全身炎症，呼吸衰竭。外显子组测序在USP 18上的一个必需剪接位点鉴定出一个纯合突变。编码的蛋白得到表达，但缺乏负调控能力。鲁索利替尼治疗后迅速持续恢复。（由沙特国王大学和其他机构资助。在USP 18中具有功能缺失突变和干扰素刺激基因的旺盛表达的新生儿用抑制干扰素信号传导的ruxolitinib进行实验性治疗。治疗开始后，儿童的临床病程有所改善。
Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.)A neonate with a loss-of-function mutation in USP18 and exuberant expression of interferon-stimulated genes was experimentally treated with ruxolitinib, which suppresses interferon signaling. The initiation of treatment was followed by an improvement in the child's clinical course.