<i>ZC3H11A</i> 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 cohort of 1015 patients with HM in adolescents, likely pathogenic missense mutations were identified in the <i>ZC3H11A</i> 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 <i>Zc3h11a</i> knockout (KO) mouse model was created. The <i>Zc3h11a^+/-</i> mice exhibited significant shifts in refraction toward myopia. Myopia-related factors, including <i>Tgfβ1, Mmp2,</i> and <i>Il6,</i> were found to be upregulated in the retina or sclera, and electroretinography and immunofluorescence staining results showed dysfunction and reduced number of bipolar cells in the retina. Transmission electron microscopy findings suggest ultrastructural abnormalities of the retina and sclera. Retinal transcriptome sequencing showed that 769 genes were differentially expressed, and <i>Zc3h11a</i> was found to have a negative impact on the PI3K-AKT and NF-κB signaling pathways by quantitative PCR and western blotting. In summary, this study characterized a new candidate pathogenic gene associated with HM and indicated that the ZC3H11A protein 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.