机构:[1]The First Affiliated Hospital of Chongqing Medical University, Chongqing, China重庆医科大学附属第一医院[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 ofChina, Chengdu 611731, China四川省人民医院[5]Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China[6]Shanghai Frontiers Science Center ofGenome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China[7]BeijingInstitute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing100730, China首都医科大学附属北京同仁医院首都医科大学附属同仁医院
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:
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
第一作者机构:[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
共同第一作者:
通讯作者:
通讯机构:[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[7]BeijingInstitute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing100730, China
推荐引用方式(GB/T 7714):
Xianyang Liu,Jiayu Meng,Xingyun Liao,et al.A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing[J].CELLULAR & MOLECULAR IMMUNOLOGY.2023,20(11):1379-1392.doi:10.1038/s41423-023-01088-9.
APA:
Xianyang Liu,Jiayu Meng,Xingyun Liao,Yusen Liu,Qian Zhou...&Shengping Hou.(2023).A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.CELLULAR & MOLECULAR IMMUNOLOGY,20,(11)
MLA:
Xianyang Liu,et al."A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing".CELLULAR & MOLECULAR IMMUNOLOGY 20..11(2023):1379-1392