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

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.

Autophagy‐mediated activation of the AIM2 inflammasome enhances M1 polarization of microglia and exacerbates retinal neovascularization

“…Briefly, in 96‐well microplates (Corning, Inc.), BV2 cells were seeded and cultivated in 100 µL medium with 5 × 10 3 cells per well. 71 Each well received 10 µL CCK‐8 reagent (MA0218, MeilunBio) under dark condition and cultured for 3 h. The optical density of individual wells was ascertained using a microplate reader obtained from ThermoFisher Scientific. The absorbance values served as indicators of cellular proliferation.…”

Role of the Atypical MAPK ERK3 in Cancer Growth and Progression

“…This effect was shown to occur at the transcript level with a decrease in IL-8 promotor activity with knockdown of ERK3. Further, a study published in 2023 noted ERK3 level was significantly increased with other inflammatoryrelated proteins when the membrane palmitoylated protein 2 (MPP2) was mutated to MPP2 K315N [23]. This process appears to require annexin A2 (ANXA2), a protein with roles in membrane trafficking and cell metastasis [24], as silencing ANXA2 reduced ERK3 protein level and alleviated MPP2-N315-induced experimental autoimmune uveoretinitis (EAU) inflammation.…”

OR11H1 Missense Variant Confers the Susceptibility to Vogt‒Koyanagi‒Harada Disease by Mediating Gadd45g Expression

“…[ 4 , 5 ] The retinal pigment epithelium (RPE) is a monolayer of pigment cells that is involved in the pathological process of VKH disease. [ 6 , 7 , 8 , 9 ] Long‐held theories suggest that the symptoms of VKH disease may be caused by an autoimmune response to melanin. [ 4 , 7 ] In the early stage of VKH disease, human melanoma cells are severely affected by T cells, presenting as folds of RPE.…”