ArticleCellular & molecular immunology2023
A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.
Article in Cellular & molecular immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 18 citations in OpenAlex.
- An Integrated Proteomics and Genomics Approach to Identify Essential Protein Kinases During Human Trophoblast Development.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- A Rare De Novo Missense Mutation in IFT122 Confers a Genetic Susceptibility Factor of Idiopathic Pediatric Uveitis Via Trio-based Whole-Exome Sequencing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Causal Relationship Between Blood Proteome and Retinitis Pigmentosa: A Mendelian Randomization Study.Translational vision science & technology · 2026Article
- Vogt-Koyanagi-Harada Syndrome: Clinical Features, Immunogenetic Predisposition and PD-1 Inhibitor-Induced Forms-A Comprehensive Review.Journal of clinical medicine · 2026Review
- Apolipoprotein E drives microglia activation in the development of autoimmune uveitis through up-regulation of peptidyl prolyl isomerase F.Science advances · 2026Article
- Integrated analysis of single-cell RNA-seq and ATAC-seq in lens epithelial cells: Unveiling the role of ATF6 as a key transcription factor.Genes & diseases · 2025Article
- Autophagy-induced NR2F1 activation promotes the apoptosis of lens epithelial cells and facilitates cataract-associated fibrosis through targeting STAT3.Genes & diseases · 2025Article
- Alterations of the Enteric Virome in Vogt-Koyanagi-Harada Disease.Investigative ophthalmology & visual science · 2025Article
- Muscone Attenuates Uveitis Through the PI3K/AKT Signaling Pathway.Investigative ophthalmology & visual science · 2025Article
- BARD1-mediated stabilization of METTL14 promotes retinal neovascularization by m6A-modifying MXD1 mRNA on a YTHDF2-dependent manner.Theranostics · 2025Article
- Identification and validation of diagnostic genesFrontiers in immunology · 2025Article
- Comparison of GWAS results between de novo tinnitus and cancer treatment-related tinnitus suggests distinctive roles for genetic risk factors.Scientific reports · 2024Article
- m6A-methylase METTL3 promotes retinal angiogenesis through modulation of metabolic reprogramming in RPE cells.Journal of neuroinflammation · 2024Article
- Transcription factor EGR2 alleviates autoimmune uveitis via activation of GDF15 to modulate the retinal microglial phenotype.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Review
- OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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