# P4HA2 Participates in Pathogenesis of Refractive Error by Regulating Collagen Posttranslational Modification and Extracellular Matrix Balance

## TL;DR

This study shows that the P4HA2 gene plays a key role in causing refractive errors like myopia by affecting collagen and extracellular matrix balance in the eye.

## Contribution

The study reveals a novel mechanism by which P4HA2 influences myopia through collagen hydroxylation and ECM imbalance.

## Key findings

- P4HA2 knockout mice showed impaired visual acuity and disrupted collagen fibril arrangement in the sclera and cornea.
- Reduced collagen hydroxylation in P4HA2 knockout models led to decreased thermal stability and ECM imbalance.
- Elevated fibronectin and reduced Collagen I levels were observed in P4HA2 knockout models.

## Abstract

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.