Sex differences in congenital hereditary endothelial dystrophy (CHED) and Slc4a11^-/- mouse model of CHED

Sex differences have been described in several corneal diseases such as Fuchs endothelial corneal dystrophy and keratoconus, with estrogens implicated in the induction of these differences. Here, we report the identification of sex differences in a cohort of 177 individuals with Corneal Hereditary Endothelial Dystrophy (CHED), a rare corneal endothelial dystrophy associated with biallelic SLC4A11 gene mutations, and in a Slc4a11^-/- mouse model of CHED.

Central corneal thickness (CCT) was measured in individuals with CHED and in Slc4a11^-/- and Slc4a11^+/+ mice to identify a correlation between sex and the degree of corneal edema. To investigate potential causes of such a correlation, RNAseq analysis and mitochondrial superoxide measurement were performed on corneal endothelium from male and female Slc4a11^-/- and Slc4a11^+/+ mice, for which body composition analysis was also performed. Gonadectomy or sham surgery was performed in Slc4a11^-/- and Slc4a11^+/+ mice at 4 weeks of age with subsequent longitudinal CCT and body weight monitoring, followed by an analysis of the interaction effect of surgery type, sex and genotype on CCT.

Male sex is associated with increased CCT, and thus more severe corneal edema, the characteristic clinical feature of CHED, in affected individuals and Slc4a11^-/- mice. The corneal endothelium in male Slc4a11^-/- mice demonstrates increased levels of oxidative stress compared to Slc4a11^-/- female mice, as evidenced by higher levels of glucose- and glutamine-derived mitochondrial superoxide, controlling for age. Removal of gonadal hormones in Slc4a11^-/- mice increases corneal edema in female mice, suggesting a protective role for ovarian hormones. Transcriptomic analysis of corneal endothelium and body composition analysis in Slc4a11^+/+ and Slc4a11^-/- mice suggest that estrogens play a role in promoting corneal endothelial utilization of lipids via β-oxidation as an alternative energy source in the absence of SLC4A11-mediated NH₃:H transport function, thereby reducing oxidative stress from glucose and glutamine metabolism.

Male sex is associated with a more severe corneal phenotype in individuals with CHED and a Slc4a11^-/- mouse model of the disease. Increased corneal edema in female Slc4a11^-/- mice following gonadectomy suggests ovarian hormones play a protective role in maintaining corneal deturgescence in the setting of loss of SLC4A11 function.