June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Sex Difference in Congenital Hereditary Endothelial Dystrophy and a Slc4a11-/- mouse model
Author Affiliations & Notes
  • Wenlin Zhang
    Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States
  • Dominic Williams
    Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States
  • Onyinye Onyia
    Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States
  • Marco Morselli
    Department of Molecular, Cell & Developmental Biology, University of California Los Angeles, Los Angeles, California, United States
  • Matteo Pellegrini
    Department of Molecular, Cell & Developmental Biology, University of California Los Angeles, Los Angeles, California, United States
  • Arthur Arnold
    Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California, United States
  • Anthony J Aldave
    Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Wenlin Zhang None; Dominic Williams None; Onyinye Onyia None; Marco Morselli None; Matteo Pellegrini None; Arthur Arnold None; Anthony Aldave None
  • Footnotes
    Support  Walton Li Chair in Cornea and Uveitis (AJA), Stotter Revocable Trust (SEI Cornea Division), P30EY000331 (core grant)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2283. doi:
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    • Get Citation

      Wenlin Zhang, Dominic Williams, Onyinye Onyia, Marco Morselli, Matteo Pellegrini, Arthur Arnold, Anthony J Aldave; Sex Difference in Congenital Hereditary Endothelial Dystrophy and a Slc4a11-/- mouse model. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2283.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We investigated the role of sex in the pathogenesis of Congenital Hereditary Endothelial Dystrophy (CHED) in published cases and in a Slc4a11-/- mouse model of CHED.

Methods : Data of age, sex and pre-operative central corneal thickness (CCT) in published cases of individuals with CHED (49 male, 29 female eyes) were collected. CCT of Slc4a11-/- (KO, 100 eyes) and Slc4a11+/+ (WT, 88) mice was monitored using AS-OCT. RNAseq analysis of in vivo corneal endothelium (CEn) from 10-week KO and WT mice (3 male and 3 female each) was carried in a 2-genotype by 2-sex matrix. Mitochondrial superoxide (Mito-O2●-) was quantified in ex vivo CEn from KO and WT mice at 10, 24 and 40 weeks (w) by oxidized MitoSOX in LC-MS.

Results : Individuals with CHED and KO mice demonstrated a progressive increase in CCT with age (p=0.026 and <0.001). Male individuals with CHED and male KO mice showed greater rate of increase in CCT than females (p=0.011 and 0.046), with no difference of CCT between male and female WT mice (p=0.945). RNAseq revealed 502 upregulated and 364 downregulated genes in CEn from KO mice compared to WT, controlling for sex. The most upregulated gene, Echdc2, encodes a mitochondrial enzyme in lipid β-oxidation. The two most downregulated genes, Cyp1b1 and Myoc, both have roles in anterior segment dysgenesis. The expression of androgen receptor (Ar) was decreased 6-fold in CEn from KO mice, but the expression of estrogen receptors (Esr1, Esr2) was unchanged. Testing genotype*sex interaction identified 86 genes influenced by Slc4a11 KO in a sexually dimorphic pattern, including an overrepresentation of genes with androgen response elements (ARE) compared to genes with ARE in the mouse genome (42% vs 22%, p=0.005). In the 86 genes, there were several regulating factors of lipid metabolism with roles in inducing sex differences: Srebf1, Insig1, Scd1, Scd4, Slc22a14, and Mir22hg. Glucose dependent Mito-O2- was significantly increased in CEn from male but not female KO mice at 24w and 40w compared to WT (p =0.029 and <0.001). Glutamine dependent Mito-O2●- was significantly increased in CEn from 40w male but not in female KO compared to 40w WT (p=0.043), and not in 10w and 24w mice.

Conclusions : Male sex is associated with more severe phenotype in individuals with CHED and in Slc4a11-/- mice. Sexually dimorphic response to Slc4a11 loss was observed at transcriptomic and functional levels in CEn of Slc4a11-/- mice.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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