De Novo Somatic Mosaicism of CYBB Caused by Intronic LINE-1 Element Insertion Resulting in Chronic Granulomatous Disease

作者全名："Yu, Lang; Li, Wenhui; Lv, Ge; Sun, Gan; Yang, Lu; Chen, Junjie; Zhou, Lina; Ding, Yuan; Zhang, Zhiyong; Tang, Xuemei; An, Yunfei; Zhao, Xiaodong"

作者地址："[Yu, Lang; Li, Wenhui; Lv, Ge; Sun, Gan; Yang, Lu; Chen, Junjie; Zhou, Lina; Ding, Yuan; Zhang, Zhiyong; Tang, Xuemei; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders Chongqin, Chongqing, Peoples R China; [Yu, Lang; Li, Wenhui; Lv, Ge; Sun, Gan; Yang, Lu; Chen, Junjie; Zhou, Lina; Ding, Yuan; Zhang, Zhiyong; Tang, Xuemei; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Minist Educ, Key Lab Child Dev & Disorders, Chongqing, Peoples R China; [Yu, Lang; Li, Wenhui; Lv, Ge; Sun, Gan; Yang, Lu; Chen, Junjie; Zhou, Lina; Ding, Yuan; Zhang, Zhiyong; Tang, Xuemei; An, Yunfei; Zhao, Xiaodong] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Zhang, Zhiyong; Tang, Xuemei; An, Yunfei] Chongqing Med Univ, Childrens Hosp, Dept Rheumatol & Immunol, Chongqing, Peoples R China"

通信作者："Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders Chongqin, Chongqing, Peoples R China.; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Minist Educ, Key Lab Child Dev & Disorders, Chongqing, Peoples R China.; Zhao, XD (通讯作者)，Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China."

来源：JOURNAL OF CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000843415300001

JCR分区：Q1

影响因子：9.1

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：CYBB; chronic granulomatous disease; de novo; somatic mosaicism; LINE-1; insertion

摘要："Chronic granulomatosis disease (CGD) is a rare inborn error of immunity, characterized by phagocytic respiratory outbreak dysfunction. Mutations causing CGD occur in CYBB on the X chromosome and in the autosomal genes CYBA, NCF1, NCF2, NCF4, RAC2, and CYBC1. Nevertheless, some patients are clinically diagnosed with CGD, due to abnormal respiratory outbursts, while the pathogenic gene mutation is unidentified. Here, we report a patient with CGD who first presented with Bacillus Calmette-Guerin disease and had recurrent pneumonia. He was diagnosed with CGD by nitro blue tetrazolium and respiratory burst tests. Detailed assessment of neutrophil activity revealed that patient neutrophils were almost entirely nonfunctional. Sanger sequencing detected a 6-kb insertion of a LINE-1 transposable element in the third intron of CYBB, leading to abnormal splicing and pseudoexon insertion, as well as introduction of a premature termination codon, resulting in predicted protein truncation. Clonal analysis demonstrated that the patient had somatic mosaicism, and the phagocytes were almost all variant CYBB, while the mosaicism rate of PBMC was about 65%. Finally, deep RNA sequencing and gp91(phox) expression analysis confirmed the pathogenicity of the mutation. In conclusion, we demonstrate that insertion of a LINE-1 transposon in a CYBB intron was responsible for CGD in our patient. Intron LINE-1 transposon element insertion should be examined in CGD patients without any known disease-causing gene mutation, in addition to identification of new genes."

基金机构：Graduate Mentor Team of Chongqing Municipal Education Commission [2019-09-66]; National Natural Science Foundation of China [82070135]; CQMU Program for Youth Innovation in Future Medicine [W0100]

基金资助正文："This work was supported by the Graduate Mentor Team of Chongqing Municipal Education Commission (Grant number 2019-09-66), the National Natural Science Foundation of China (Grant number 82070135), and the CQMU Program for Youth Innovation in Future Medicine (W0100)."