A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing

作者全名："Liu, Xianyang; Meng, Jiayu; Liao, Xingyun; Liu, Yusen; Zhou, Qian; Xu, Zongren; Yin, Shuming; Cao, Qingfeng; Su, Guannan; He, Siyuan; Li, Wanqian; Wang, Xiaotang; Wang, Guoqing; Li, Dali; Yang, Peizeng; Hou, Shengping"

作者地址："[Liu, Xianyang; Meng, Jiayu; Liao, Xingyun; Liu, Yusen; Zhou, Qian; Xu, Zongren; Cao, Qingfeng; Su, Guannan; He, Siyuan; Li, Wanqian; Wang, Xiaotang; Wang, Guoqing; Yang, Peizeng; Hou, Shengping] Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China; [Liu, Xianyang; Meng, Jiayu; Liao, Xingyun; Liu, Yusen; Zhou, Qian; Xu, Zongren; Cao, Qingfeng; Su, Guannan; He, Siyuan; Li, Wanqian; Wang, Xiaotang; Wang, Guoqing; Yang, Peizeng; Hou, Shengping] Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China; [Liu, Xianyang; Meng, Jiayu; Liao, Xingyun; Liu, Yusen; Zhou, Qian; Xu, Zongren; Cao, Qingfeng; Su, Guannan; He, Siyuan; Li, Wanqian; Wang, Xiaotang; Wang, Guoqing; Yang, Peizeng; Hou, Shengping] Chongqing Eye Inst, Chongqing, Peoples R China; [Meng, Jiayu] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 611731, Peoples R China; [Liao, Xingyun] Chongqing Univ, Canc Hosp, Dept Med Oncol, Chongqing 400030, Peoples R China; [Yin, Shuming; Li, Dali] East China Normal Univ, Shanghai Frontiers Sci Ctr Genome Editing & Cell, Shanghai Key Lab Regulatory Biol, Sch Life Sci, Shanghai 200241, Peoples R China; [Hou, Shengping] Capital Med Univ, Beijing Tongren Hosp, Beijing Ophthalmol & Visual Sci Key Lab, Beijing Inst Ophthalmol,Beijing Tongren Eye Ctr, Beijing 100730, Peoples R China"

通信作者："Yang, PZ; Hou, SP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing, Peoples R China.; Yang, PZ; Hou, SP (通讯作者)，Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China.; Yang, PZ; Hou, SP (通讯作者)，Chongqing Eye Inst, Chongqing, Peoples R China.; Hou, SP (通讯作者)，Capital Med Univ, Beijing Tongren Hosp, Beijing Ophthalmol & Visual Sci Key Lab, Beijing Inst Ophthalmol,Beijing Tongren Eye Ctr, Beijing 100730, Peoples R China."

来源：CELLULAR & MOLECULAR IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001080581400001

JCR分区：Q1

影响因子：21.8

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Vogt-Koyanagi-Harada disease; Whole exome sequencing; De novo mutation; Membrane palmitoylated protein 2; Annexin A2; ERK3/IL-17E pathway

摘要："Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1 beta, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC-MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease."

基金机构："We thank the families for participation in this study, and we thank Novogene Technology Co., Ltd., for the WES sequencing and analysis. This work was supported by the National Natural Science Foundation Project of China (82070951, 82271078), the National N [82070951, 82271078]; National Natural Science Foundation Project of China [81930023]; National Natural Science Foundation Key Program [CXQT19015]; Innovative Research Group Project of Chongqing Education Commission [cx2018010]; Innovation Supporting Plan of Overseas Study of Chongqing; National Key Clinical Specialties Construction Program of China; Chongqing Branch of the National Clinical Research Center for Ocular Diseases [2008CA5003]; Chongqing Key Laboratory of Ophthalmology (CSTC) [w0047]; Program for Youth Innovation in Future Medicine, Chongqing Medical University"

基金资助正文："We thank the families for participation in this study, and we thank Novogene Technology Co., Ltd., for the WES sequencing and analysis. This work was supported by the National Natural Science Foundation Project of China (82070951, 82271078), the National Natural Science Foundation Key Program (81930023), The Innovative Research Group Project of Chongqing Education Commission (CXQT19015), the Innovation Supporting Plan of Overseas Study of Chongqing (cx2018010), the National Key Clinical Specialties Construction Program of China, the Chongqing Branch of the National Clinical Research Center for Ocular Diseases, the Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003) and the Program for Youth Innovation in Future Medicine, Chongqing Medical University (w0047)."