ZC3H11A mutations cause high myopia by triggering PI3K-AKT and NF-κB mediated signaling pathway in humans and mice
Abstract
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 theZC3H11Agene 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, aZc3h11aknock-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, andZc3h11awas found to have a negative impact on the PI3K-AKT and NF-κB signaling 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 candidate pathogenic gene associated with high myopia, and indicated that theZC3H11Aprotein may serve as a stress-induced nuclear response trigger, and its abnormality causes disturbances in a series of inflammatory and myopic factors. These findings offer potential therapeutic intervention targets for controlling the development of HM.
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