Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition.
Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition.
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DOI：
10.3389/fimmu.2023.1287258
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
ISG 15缺乏症是一种罕见的疾病，由编码ISG 15蛋白的ISG 15基因中的常染色体隐性变异引起。ISG 15蛋白在I型和II型干扰素（IFN）免疫途径中起双重作用。在细胞外，ISG 15蛋白是IFN-γ依赖性抗分枝杆菌免疫所必需的，而在细胞内，ISG 15是USP 18介导的IFN-α/β信号转导下调所必需的。由于这种双重作用，ISG 15缺陷可表现为各种临床表型，从对分枝杆菌感染的易感性到以坏死性皮肤病变、脑内钙化和肺部受累为特征的自身炎症。在这份报告中，我们描述了在两个不同家族中发现的导致完全ISG 15缺乏和严重皮肤溃疡的新变体。全外显子组测序鉴定了第一个家族先证者的杂合错义p.Q16X ISG 15变体和杂合多基因1p36.33缺失。在第二个家庭中，在两个兄弟姐妹中检测到纯合的ISG 15基因缺失。我们还进行了进一步的分析，包括细胞因子失调，干扰素刺激的基因表达，和p-STAT 1在淋巴细胞和病变组织中的激活的特征。最后，我们证明了与ISG 15缺乏症相关的临床症状在第二个家庭的一个兄弟姐妹与Janus激酶（JAK）抑制剂baricitinib治疗后完全和快速解决。
ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/β signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.
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DOI：
10.1038/s41577-021-00633-9
发表时间：
2022-08
期刊：
Nature reviews. Immunology
影响因子：
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作者：
Crow YJ;Stetson DB
通讯作者：
Stetson DB
DOI：
10.1093/bioinformatics/bts526
发表时间：
2012-11-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Plagnol V;Curtis J;Epstein M;Mok KY;Stebbings E;Grigoriadou S;Wood NW;Hambleton S;Burns SO;Thrasher AJ;Kumararatne D;Doffinger R;Nejentsev S
通讯作者：
Nejentsev S
DOI：
10.1126/science.1224026
发表时间：
2012-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bogunovic D;Byun M;Durfee LA;Abhyankar A;Sanal O;Mansouri D;Salem S;Radovanovic I;Grant AV;Adimi P;Mansouri N;Okada S;Bryant VL;Kong XF;Kreins A;Velez MM;Boisson B;Khalilzadeh S;Ozcelik U;Darazam IA;Schoggins JW;Rice CM;Al-Muhsen S;Behr M;Vogt G;Puel A;Bustamante J;Gros P;Huibregtse JM;Abel L;Boisson-Dupuis S;Casanova JL
通讯作者：
Casanova JL
影响因子：
158.5
作者：
Alsohime, Fahad;Martin-Fernandez, Marta;Alangari, Abdullah A.
通讯作者：
Alangari, Abdullah A.
影响因子：
10.6
作者：
通讯作者：
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