ISG15缺乏症是由ISG15基因的常染色体隐性变异引起的一种罕见疾病,它编码ISG15蛋白。ISG15蛋白在I型和II型干扰素(IFN)免疫途径中起双重作用。细胞外,ISG15蛋白对于依赖IFN-γ的抗分枝杆菌免疫是必不可少的,而在细胞内,ISG15对于USP18介导的IFN-α/β信号传导的下调是必需的。由于这个双重角色,ISG15缺乏症可以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为特征的自身炎症,脑内钙化,和肺部受累。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ISG15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中的杂合错义p.Q16XISG15变体和杂合多基因1p36.33缺失。在第二个家庭,在两个兄弟姐妹中检测到纯合的总ISG15基因缺失。我们还进行了进一步的分析,包括细胞因子失调的特征,干扰素刺激的基因表达,淋巴细胞和病变组织中的p-STAT1激活。最后,我们证明,在使用Janus激酶(JAK)抑制剂baricitinib治疗后,第二家族的一个同胞与ISG15缺乏相关的临床症状得到了完全和快速的缓解.
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.