ZC3H11A mutations cause high myopia by triggering PI3K-AKT and NF-κB mediated inflammatory reactions in humans and mice

High myopia (HM) is a severe form of refractive error that results in irreversible visual impairment and even blindness. However, the genetic and pathological mechanisms underlying this condition are not yet fully understood. From a adolescents myopia survey cohort of 1015 HM patients, pathogenic missense mutations were identified in the ZC3H11A gene in four patients by whole exome sequencing. This gene is a zinc finger and stress-induced protein that plays a significant role in regulating nuclear mRNA export. To better understand the function and molecular pathogenesis of myopia in relation to gene mutations, a Zc3h11a knock-out (KO) mouse model was created. The heterozygous KO (Het-KO) mice exhibited significant shifts in vision towards myopia. Electroretinography revealed that the b-wave amplitude was significantly lower in these mice under dark adaptation. Using immunofluorescence antibodies against specific retinal cell types, the density of bipolar cell-labelled proteins was found to be decreased. Transmission electron microscopy findings suggesting ultrastructural abnormalities of the retina and sclera. Retinal transcriptome sequencing showed that 769 genes were differentially expressed, and Zc3h11a was found to have a negative impact on the PI3K-AKT and NF-κB signalling pathways by quantitative PCR and western blotting. In addition, myopia-related factors, including TGF-β1, MMP-2 and IL-6 were found to be upregulated in the retina or sclera. In summary, this study characterized a new pathogenic gene associated with HM. The findings indicated that the ZC3H11A protein may serve as an innate immune and inflammatory response trigger, contributing to the early onset of myopia. These findings offer potential therapeutic intervention targets for controlling the development of HM.