# Analysis of Keratoconus-Related Phenotypes in Two Pcsk1 Mouse Models

## TL;DR

This study investigated whether mutations in the Pcsk1 gene cause corneal changes linked to keratoconus in mice, but found no significant differences between mutant and control mice.

## Contribution

The study provides new evidence that Pcsk1 mutations alone may not cause keratoconus-related corneal phenotypes in mice.

## Key findings

- No significant differences in corneal thickness or morphology were found between Pcsk1 mutant and control mice.
- Neither the N222D mutation nor the Pcsk1 knockout affected the corneal phenotype in the tested mouse models.
- The Pcsk1 gene may require additional genetic or environmental factors to contribute to keratoconus.

## Abstract

Previously, a variant within the Pcsk1 gene was found to segregate with the keratoconus (KC) phenotype in whole genome sequencing of a four-generation family. We aimed to evaluate a potential relation between the Pcsk1 gene and corneal phenotype in mouse models.

Two strains of Pcsk1 mice, one with a knockout (KO) and one with an N222D point mutation, were bred. Central corneal thickness (CCT) was determined using spectral domain optical coherence tomography (SD-OCT) in PC1/3+/+ (n = 12), PC1/3+/K^ (n = 14), PC1/3K^/K^ (n = 5), PC1+/+ (n = 8), PC1+/ N222D (n = 15), and PC1 N222D / N222D (n = 7) mice at 3 and 6 months of age. Pachymetry maps were generated using the Mouse Corneal Analysis Program (MCAP) to process OCT images. Hematoxylin and eosin (H&E) staining using corneal sections from these animals were used to examine morphological changes.

No significant differences in corneal CCT, pachymetry, or morphology were observed among any of the mutant mice compared with their control littermates.

In this setting, neither the N222D point mutation nor the Pcsk1 KO affected the corneal phenotype in two mouse models. The Pcsk1 gene could contribute to keratoconus when paired with additional genetic and environmental factors, not included in this study.

Genetic factors are known to contribute to the pathogenesis of keratoconus. Although a variant in the Pcsk1 gene has been shown to segregate with keratoconus in a family, there is yet no evidence of Pcsk1 gene mutation correlating with pathogenic corneal phenotype in mouse models.