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

机构地区：[1]The First Affiliated Hospital of Chongqing Medical University,Chongqing,China [2]Chongqing Key Laboratory of Ophthalmology,Chongqing,China [3]Chongqing Eye Institute,Chongqing,China [4]Sichuan Provincial Key Laboratory for Human Disease Gene Study,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu,611731,China [5]Department of Medical Oncology,Chongqing University Cancer Hospital,Chongqing,400030,China [6]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy,Shanghai Key Laboratory of Regulatory Biology,School of Life Sciences,East China Normal University,Shanghai,200241,China [7]Beijing Institute of Ophthalmology,Beijing Tongren Eye Center,Beijing Tongren Hospital,Capital Medical University,Beijing Ophthalmology&Visual Sciences Key Laboratory,Beijing,100730,China

出　　处：《Cellular & Molecular Immunology》2023年第11期1379-1392,共14页中国免疫学杂志（英文版）

基　　金：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);the Program for Youth Innovation in Future Medicine,Chongqing Medical University(w0047).

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-1β,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.

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

分 类 号：R77[医药卫生—眼科]