A novel homozygous Y140X mutation of ISG15 causes diverse type I interferonopathies in sibling patients with cutaneous lesions or recurrent parenchymal pneumonia

作者全名："Xu, Qiling; Li, Wenyan; Zhao, Qian; Zhao, Lu; Lv, Ge; Sun, Gan; Gao, Yelei; Ding, Yuan; Zhang, Zhiyong; Zhou, Lina; Chen, Yongwen; Tang, Xuemei; Zhu, Jin; Zhao, Xiaodong; An, Yunfei"

作者地址："[Xu, Qiling; Zhao, Qian; Zhao, Lu; Lv, Ge; Sun, Gan; Gao, Yelei; Ding, Yuan; Zhang, Zhiyong; Zhou, Lina; Tang, Xuemei; Zhu, Jin; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders Chongqing, Childrens Hosp, Chongqing, Peoples R China; [Xu, Qiling; Zhao, Qian; Lv, Ge; Sun, Gan; Gao, Yelei; Ding, Yuan; Zhang, Zhiyong; Zhou, Lina; Tang, Xuemei; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Minist Educ, Key Lab Child Dev & Disorders, Childrens Hosp, Chongqing, Peoples R China; [Xu, Qiling; Li, Wenyan; Zhao, Qian; Lv, Ge; Sun, Gan; Gao, Yelei; Ding, Yuan; Zhang, Zhiyong; Zhou, Lina; Tang, Xuemei; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Chongqing Key Lab Child Infect & Immun, Childrens Hosp, Chongqing, Peoples R China; [Zhang, Zhiyong; Tang, Xuemei; An, Yunfei] Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China; [Zhu, Jin] Chongqing Med Univ, Coll Basic Med, Mol Med Diagnost & Testing Ctr 6, Dept Pathol, Chongqing, Peoples R China; [Chen, Yongwen; Zhu, Jin] Third Mil Med Univ, Inst Immunol, PLA, Chongqing 400014, Peoples R China"

通信作者："Zhao, XD; An, YF (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders Chongqing, Childrens Hosp, Chongqing, Peoples R China.; An, YF (通讯作者)，Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, Chongqing, Peoples R China."

来源：CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001125783300001

JCR分区：Q2

影响因子：4.5

年份：2023

卷号：257

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：IFN-stimulated gene 15 (ISG15); STAT; IFN-I; Recurrent Pneumonia; JAK inhibitor

摘要："Purpose: Interferon-stimulated gene 15 (ISG15) deficiency, a rare human inborn error of immunity characterized by susceptibility to Bacillus Calmette-Guerin (BCG) diseases, neuropathic and dermatological manifestations. Methods: The clinical and immunological features of two siblings with ISG15 deficiency combined with asymptomatic myeloperoxidase (MPO) mutations were analyzed, and their pathogenesis, as well as target therapeutic candidates, were explored. Results: The manifestation in patient 2 was skin lesions, while those in patient 1 were intracranial calcification and recurrent pneumonia. Whole-exome identified novel, dual mutations in ISG15 and MPO. PBMCs and B cell lines derived from the patients showed hyper-activated JAK/STAT signaling. Normal neutrophil function excluded pathogenicity caused by the MPO mutation. RNA sequencing identified baricitinib as therapeutic candidate. Conclusions: We report two sibling patients harboring the same novel ISG15 mutation showing diverse clinical features, and one harbored a rare phenotype of pneumonia. These findings expand the clinical spectrum of ISG15 deficiency and identify baricitinib as therapeutic candidate."

基金机构："National Natural Science Foundation of China [82070135, 82202011]; National Key Research and Development Program of China [2021YFC2700804]; Postgraduate Tutor Team Project of Chongqing Municipal Education Commission (Education Research and Development Program of Chongqing) [2019-9-66]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant number 82070135 and 82202011) , the National Key Research and Development Program of China (2021YFC2700804) , and the Postgraduate Tutor Team Project of Chongqing Municipal Education Commission (Education Research and Development Program of Chongqing: 2019-9-66) ."