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

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外文摘要：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.

外文关键词：

Vogt-Koyanagi-Harada diseaseWhole exome sequencingDe novo mutationMembrane palmitoylated protein 2Annexin A2ERK3/IL-17E pathway

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

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作者单位：

The First Affiliated Hospital of Chongqing Medical University,Chongqing,China

Chongqing Key Laboratory of Ophthalmology,Chongqing,China

Chongqing Eye Institute,Chongqing,China

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

Department of Medical Oncology,Chongqing University Cancer Hospital,Chongqing 400030,China

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

Beijing Institute of Ophthalmology,Beijing Tongren Eye Center,Beijing Tongren Hospital,Capital Medical University,Beijing Ophthalmology&Visual Sciences Key Laboratory,Beijing 100730,China

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基金：

National Natural Science Foundation Project of ChinaNational Natural Science Foundation Project of ChinaNational Natural Science Foundation Key ProgramInnovative Research Group Project of Chongqing Education CommissionInnovation Supporting Plan of Overseas Study of ChongqingNational Key Clinical Specialties Construction Program of ChinaChongqing Branch of the National Clinical Research Center for Ocular DiseasesChongqing Key Laboratory of Ophthalmology(CSTC)Program for Youth Innovation in Future Medicine,Chongqing Medical University

项目编号：

820709518227107881930023CXQT19015cx20180102008CA5003w0047

出版年：

2023

DOI：

10.1038/s41423-023-01088-9

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(11)

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