P4HA2 Participates in Pathogenesis of Refractive Error by Regulating Collagen Posttranslational Modification and...

Myopia represents a refractive anomaly characterized by impaired vision resulting from a misfocused image in front of the fovea. Although numerous genes linked to high myopia (HM) have been identified, the exact etiology and pathogenesis mechanisms of HM remain predominantly obscure. In a prior investigation, a mutation in the P4HA2 gene was identified in association with HM. To illuminate the potential mechanisms of action of P4HA2 in HM, we established a P4HA2-knockout mouse line (P4ha2 ^-/-) and a P4HA2-knockout HEK293 cell line for this study. P4ha2 ^-/- mice exhibited compromised visual acuity and altered light transmission pathways as evidenced by multiple biometric assessments. Furthermore, we observed a time-dependent disruption in the arrangement of collagen fibrils in the sclera and cornea of the P4ha2 ^-/- mice, attributed to diminished thermal stability due to decreased collagen hydroxylation. Our findings also revealed elevated fibronectin levels and reduced Collagen I expression in the sclera and cornea of the P4ha2 ^-/- mice, as well as in P4HA2-knockout HEK293 cells, suggesting an imbalance in extracellular matrix (ECM) components that could further perturb light transmission pathways, which induced HM-associated refractive error. In summary, P4HA2 contributes significantly to the pathogenesis and progressive deterioration of refractive error by accelerating collagen degeneration via reduced collagen hydroxylation.