Investigative Ophthalmology & Visual Science Cover Image for Volume 65, Issue 7
June 2024
Volume 65, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2024
Systematic ocular phenotyping of knockout mouse lines identifies genes associated with age-related corneal dystrophies
Author Affiliations & Notes
  • Andrew Briere
    Touro University California, Vallejo, California, United States
  • Peter Vo
    California Northstate University College of Medicine, Elk Grove, California, United States
  • Michel Roux
    Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Grafenstaden, Grand Est, France
  • Dave Clary
    Mouse Biology Program, University of California Davis, Davis, California, United States
  • Denise M Imai-Leonard
    Comparitive Pathology Laboratory, University of California Davis School of Veterinary Medicine, Davis, California, United States
  • International Mouse Phenotyping Consortium
    University of California Davis, Davis, California, United States
  • Brian Leonard
    Department of Surgical Sciences, University of California Davis, Davis, California, United States
  • KC Kent Lloyd
    Mouse Biology Program, University of California Davis, Davis, California, United States
  • Colin McKerlie
    The Hospital for Sick Children, Toronto, Ontario, Canada
  • Ala Moshiri
    Ophthalmolgy, University of California Davis School of Medicine, Sacramento, California, United States
  • Footnotes
    Commercial Relationships   Andrew Briere None; Peter Vo None; Michel Roux None; Dave Clary None; Denise Imai-Leonard None; International Mouse Phenotyping Consortium None; Brian Leonard None; KC Kent Lloyd None; Colin McKerlie None; Ala Moshiri None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2024, Vol.65, 2795. doi:
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      Andrew Briere, Peter Vo, Michel Roux, Dave Clary, Denise M Imai-Leonard, International Mouse Phenotyping Consortium, Brian Leonard, KC Kent Lloyd, Colin McKerlie, Ala Moshiri; Systematic ocular phenotyping of knockout mouse lines identifies genes associated with age-related corneal dystrophies. Invest. Ophthalmol. Vis. Sci. 2024;65(7):2795.

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

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Abstract

Purpose : Corneal dysmorphologies (CD) encompass a spectrum of conditions, including regressive degeneration corneal dystrophies (CDtrs) and corneal dysplasias (CDyps) driven by defective growth and differentiation. These conditions may manifest at various life stages, including congenitally and in adulthood. This study aimed to investigate specific genes contributing to late onset CD in aged mice, with potential implications for age-related CD development in humans.

Methods : The IMPC database, housing 8,483 knockout mouse lines, was filtered to focus only on late adult mice (aged 49 weeks or older) with significant (p<0.0001) CD phenotypes. To focus on late-onset abnormalities, mouse lines with corneal phenotypes in early adulthood (age 16 weeks) were excluded. Candidate genes were matched with human orthologs using Mouse Genome Informatics (MGI), and a literature review explored prior CD associations. Comparative analyses between candidate CD genes from the IMPC and established human CD genes included protein-protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG).

Results : The analysis revealed 27 late-stage candidate CD genes associated with abnormal corneal phenotypes not seen in early adulthood. Of these 27, four had prior CD associations, including 3 in humans and 1 in mice. Twenty-three (23) candidate CD genes were novel. Predictive protein-protein relationships using STRING suggested several interactions, including connections with established human CD genes. PANTHER analysis identified 11 biological processes categories, with 3 unique to candidate genes and 8 shared with gold standard human CD genes. Several late-stage CD candidate genes were involved in biological pathways established in human corneal disease, such as TGF-beta signaling, regulation of actin cytoskeleton, cellular senescence, and protein digestion and absorption.

Conclusions : This study identified 27 genes resulting in late-stage corneal phenotypes in knockout mice, 23 of which are only now implicated in corneal biology. These genes may represent potential therapeutic targets for preventing or treating corneal diseases in aging human populations.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Corneal photography of late stage knockout mice with significant CD phenotypes. Wild type in top left for comparison

Corneal photography of late stage knockout mice with significant CD phenotypes. Wild type in top left for comparison

 

Protein-protein analysis between 26 candidate late-stage CD genes (red), and 42 established human CD genes (gold)

Protein-protein analysis between 26 candidate late-stage CD genes (red), and 42 established human CD genes (gold)

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