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

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

  • Cell Mol Immunol. 2023 Oct 12. doi: 10.1038/s41423-023-01088-9.
Xianyang Liu # 1 2 3,  Jiayu Meng # 1 2 3 4,  Xingyun Liao # 1 2 3 5,  Yusen Liu # 1 2 3,  Qian Zhou 1 2 3,  Zongren Xu 1 2 3,  Shuming Yin 6,  Qingfeng Cao 1 2 3,  Guannan Su 1 2 3,  Siyuan He 1 2 3,  Wanqian Li 1 2 3,  Xiaotang Wang 1 2 3,  Guoqing Wang 1 2 3,  Dali Li 6,  Peizeng Yang 7 8 9,  Shengping Hou 10 11 12 13
Affiliations

Affiliations

  • 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 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. peizengycmu@126.com.
  • 8 Chongqing Key Laboratory of Ophthalmology, Chongqing, China. peizengycmu@126.com.
  • 9 Chongqing Eye Institute, Chongqing, China. peizengycmu@126.com.
  • 10 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. sphou828@163.com.
  • 11 Chongqing Key Laboratory of Ophthalmology, Chongqing, China. sphou828@163.com.
  • 12 Chongqing Eye Institute, Chongqing, China. sphou828@163.com.
  • 13 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China. sphou828@163.com.
  • # Contributed equally.
PMID: 37828081 DOI: 10.1038/s41423-023-01088-9
Abstract

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.

Keywords

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

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