Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.
Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.
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DOI：
10.1084/jem.20151529
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发表时间：
2016-06-27
期刊：
影响因子：
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通讯作者：
Mancini GM
中科院分区：
文献类型：
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作者：
Meuwissen ME;Schot R;Buta S;Oudesluijs G;Tinschert S;Speer SD;Li Z;van Unen L;Heijsman D;Goldmann T;Lequin MH;Kros JM;Stam W;Hermann M;Willemsen R;Brouwer RW;Van IJcken WF;Martin-Fernandez M;de Coo I;Dudink J;de Vries FA;Bertoli Avella A;Prinz M;Crow YJ;Verheijen FW;Pellegrini S;Bogunovic D;Mancini GM
Meuwissen及其合作者定义了假性TORCH综合征的一种新的遗传原因，该综合征类似于先天性感染的后遗症，代表了一种新的I型干扰素病。假性TORCH综合征（PTS）的特征是小头畸形、脑室扩大、脑钙化，偶尔也有出生时类似先天性感染后遗症的全身特征，但没有感染原。遗传缺陷导致1型干扰素（IFN）反应的激活已被证明是导致Aicardi-Goutières综合征的原因，这是PTS的一个原因。泛素特异性肽酶18（USP 18）是I型IFN信号传导的关键负调节剂。在这项研究中，我们确定了USP 18的功能丧失的隐性突变在5个PTS患者从两个无关的家庭。离体脑尸检材料显示先天性免疫炎症伴钙化和多小脑回。在体外，患者成纤维细胞显示出严重增强的IFN诱导的炎症，这完全被USP 18的慢病毒转导所挽救。这些发现将USP 18缺陷添加到统称为I型干扰素病的遗传性疾病列表中。此外，USP 18缺陷代表了由对I型IFN的应答失调引起的PTS的第一种遗传性疾病。在治疗上，这使USP 18不仅成为遗传性而且也成为获得性IFN介导的CNS疾病的有希望的靶点。
Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy. Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.