Newly revealed variants of SERPINA3 in generalized pustular psoriasis attenuate inhibition of ACT on cathepsin G

作者全名："Liu, Yaqin; Li, Hongmei; Meng, Shasha; Xu, Yunfei; Ni, Sili; Sun, Yanan; Zhou, Weihui"

作者地址："[Liu, Yaqin; Meng, Shasha; Xu, Yunfei; Sun, Yanan; Zhou, Weihui] Chongqing Med Univ, Pediat Res Inst, Chongqing, Peoples R China; [Liu, Yaqin; Meng, Shasha; Xu, Yunfei; Sun, Yanan; Zhou, Weihui] Chongqing Med Univ, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Chongqing, Peoples R China; [Liu, Yaqin; Meng, Shasha; Xu, Yunfei; Sun, Yanan; Zhou, Weihui] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing, Peoples R China; [Liu, Yaqin; Meng, Shasha; Xu, Yunfei; Sun, Yanan; Zhou, Weihui] Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China; [Li, Hongmei; Ni, Sili] Chongqing Med Univ, Childrens Hosp, Dept Dermatol, Chongqing, Peoples R China"

通信作者："Zhou, WH (通讯作者)，Chongqing Med Univ, Pediat Res Inst, Chongqing, Peoples R China.; Zhou, WH (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Chongqing, Peoples R China.; Zhou, WH (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing, Peoples R China.; Zhou, WH (通讯作者)，Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China."

来源：JOURNAL OF HUMAN GENETICS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000939343300001

JCR分区：Q2

影响因子：2.6

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Generalized pustular psoriasis (GPP) is an autoinflammatory skin disease whose pathogenesis has not yet been fully elucidated. Alpha-1-antichymotrypsin(ACT) is a protein encoded by the SERPINA3 gene and an inhibitor of cathepsin G. One study of a European sample suggested that the loss of ACT function caused by SERPINA3 mutation is implicated in GPP. However, the role of SERPINA3 in the pathogenesis of GPP in other ethnic populations is unclear. To explore this, seventy children with GPP were performed next-generation sequencing to identify rare variants in the SERPINA3 gene. Bioinformatic analysis and functional tests were used to determine the effects of the variants, and a comprehensive analysis was performed to determine the pathogenicity of the variants and whether they are associated with GPP. One rare deletion and three rare missense variants were identified in the SERPINA3 gene in GPP. The deletion variant c.1246_1247del was found to result in a mutant protein with an extension of 10 amino acids and a C-terminal of 20 amino acids that was completely different from the wild-type. This mutant was found to impede secretion of ACT, thus failing to function as an inhibitor of cathepsin G. Two missense variants were found to reduce the ability of ACT to inhibit cathepsin G enzymatic activity. The association analysis suggested that the deletion variant is associated with GPP. This study identified four rare novel mutations of SERPINA3 and demonstrated that three of these mutations result in loss of function, contributing to the pathogenesis of pediatric-onset GPP in the Asian population."

基金机构："Clinical research project of Children's Hospital of Chongqing Medical University [6000052]; National Natural Science Foundation of China [81070269, 81571388]; Natural Science Foundation of Chongqing, China [cstc2021jcyj-msxmX0244]; General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders [GBRP-202114]"

基金资助正文："Supported partially by the Clinical research project of Children's Hospital of Chongqing Medical University (Grant no. 6000052 to H.L.) and the National Natural Science Foundation of China (Grant nos. 81070269 and 81571388 to W.Z.). the Natural Science Foundation of Chongqing, China (Grant No. cstc2021jcyj-msxmX0244 to S.M.) and the General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders (Grant No. GBRP-202114 to S.M.)."