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

PURPOSE: 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.

METHODS

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.

RESULTS

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

CONCLUSIONS

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.

TRANSLATIONAL RELEVANCE: 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.