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. 2025 May 1;66(5):7.
doi: 10.1167/iovs.66.5.7.

Systematic Ocular Phenotyping of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies

Andrew Briere  1 , Peter Vo  2 , Benjamin Yang  3 , David Adams  4 , Takanori Amano  5 , Oana Amarie  6 , Zorana Berberovic  7 , Lynette Bower  8 , Steve D M Brown  9 , Samantha Burrill  10 , Soo Young Cho  11 , Sharon Clementson-Mobbs  9 , Abigail D'souza  7 , Mohammad Eskandarian  7 , Ann M Flenniken  7 , Helmut Fuchs  6 , Valerie Gailus-Durner  6 , Yann Hérault  12 , Martin Hrabe de Angelis  6   13   14 , Shundan Jin  5 , Russell Joynson  9 , Yeon Kyung Kang  15 , Haerim Kim  15 , Hiroshi Masuya  5 , Hamid Meziane  12 , Ki-Hoan Nam  16 , Hyuna Noh  15 , Lauryl M J Nutter  17 , Marcela Palkova  18 , Jan Prochazka  18 , Miles Joseph Raishbrook  18 , Fabrice Riet  12 , Jason Salazar  8 , Radislav Sedlacek  18 , Mohammed Selloum  12 , Kyoung Yul Seo  19 , Je Kyung Seong  20 , Hae-Sol Shin  19 , Toshihiko Shiroishi  5 , Michelle Stewart  9 , Karen Svenson  10 , Masaru Tamura  5 , Heather Tolentino  8 , Sara Wells  9 , Wolfgang Wurst  21 , Atsushi Yoshiki  5 , Louise Lanoue  8 , K C Kent Lloyd  8   22 , Brian C Leonard  23 , Michel J Roux  12 , Colin McKerlie  17   24 , Ala Moshiri  25 ; International Mouse Phenotyping Consortium
Affiliations

Systematic Ocular Phenotyping of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies

Andrew Briere et al. Invest Ophthalmol Vis Sci. .

Abstract

Purpose: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans.

Methods: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG).

Results: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence.

Conclusions: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

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Conflict of interest statement

Disclosure: A. Briere, None; P. Vo, None; B. Yang, None; D. Adams, None; T. Amano, None; O. Amarie, None; Z. Berberovic, None; L. Bower, None; S.D.M. Brown, None; S. Burrill, None; S.Y. Cho, None; S. Clementson-Mobbs, None; A. D'souza, None; M. Eskandarian, None; A.M. Flenniken, None; H. Fuchs, None; V. Gailus-Durner, None; Y. Hérault, None; M. Hrabe de Angelis, None; S. Jin, None; R. Joynson, None; Y.K. Kang, None; H. Kim, None; H. Masuya, None; H. Meziane, None; K.-H. Nam, None; H. Noh, None; L.M.J. Nutter, None; M. Palkova, None; J. Prochazka, None; M.J. Raishbrook, None; F. Riet, None; J. Salazar, None; R. Sedlacek, None; M. Selloum, None; K.Y. Seo, None; J.K. Seong, None; H.-S. Shin, None; T. Shiroishi, None; M. Stewart, None; K. Svenson, None; M. Tamura, None; H. Tolentino, None; S. Wells, None; W. Wurst, None; A. Yoshiki, None; L. Lanoue, None; K.C.K. Lloyd, None; B.C. Leonard, None; M.J. Roux, None; C. McKerlie, None; A. Moshiri, None

Figures

Figure 1.
Figure 1.
External color photography of corneas from late-stage knockout mice with documented cornea abnormalities. Top row: WT, Abhd17b−/−, Ik+/−. Bottom row: Slc30a7+/−. Sprr1a−/−, Tenm4−/−.
Figure 2.
Figure 2.
STRING protein–protein analysis between human ortholog proteins of 13 candidate LACD genes (red), 47 established human CD proteins (gold), and 10 additional interactor proteins determined by STRING (green). Candidate LACD gene Abca16 and established human CD gene MIR-184 were omitted from this analysis as they are not available in STRING. Analysis run with modified settings (Organism: Homo Sapiens; Network Type = full STRING network; Confidence cutoff 0.40; Additional interactors 10). Darker edges indicate stronger protein–protein interaction.
Figure 3.
Figure 3.
Biological process categories of 13 candidate LACD genes (top) and 47 established human CD genes (bottom) using PANTHER analysis. Candidate LACD gene Abca16 and established human CD gene MIR-184 were not included in the analysis as they were not available on PANTHER. Gold star depicts biological processes found in both candidate LACD genes and established CD genes.
Figure 4.
Figure 4.
cGMP-PKG signaling pathway highlighting candidate LACD gene Rgs2 (red star), established CD genes CNA1 (gold star), and two additional STRING interactor genes INS and AKT1 (green star).
See this image and copyright information in PMC

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