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Aarthi Krishnan, Adam Faranda, Samuel G Novo, Yan Wang, Melinda K Duncan; Bioinformatic Analysis reveals possible mechanisms of Aniridic Keratopathy. Invest. Ophthalmol. Vis. Sci. 2021;62(8):710.
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© ARVO (1962-2015); The Authors (2016-present)
Aniridic Keratopathy is a sight threatening manifestation of Aniridia, a genetic disease caused by Pax6 haploinsufficiency. However, the mechanisms underlying this keratopathy remain unclear. We performed unbiased transcriptome profiling of PAX6 mutant mouse corneas to understand the mechanisms involved in Aniridic Keratopathy.
RNA was isolated from PAX6 mutant (+/-) and wildtype corneas obtained from 20 week old mice (3 biological replicates of each) and transcriptome profiling performed by RNAseq. Differentially expressed genes (DEGs) were identified using bioinformatic pipelines and altered pathways identified via iPathway Guide (https://advaitabio.com/). DEGs in the Pax6 mutant cornea were compared to those obtained from prior corneal gene expression profiles including those differentially expressed between human cornea and conjunctiva (GEO Accession GSE38190). L1000CDS2 analysis was performed on the LINCS server (https://lincsproject.org/)
A total of 823 genes (514 upregulated and 309 downregulated) were differentially expressed in the 20-week-old PAX6 mutant mouse cornea. Inflammation, cytokine-cytokine receptors and angiogenesis were the most upregulated pathways in PAX6 mutant corneas. Conjunctival cytokeratins upregulate in the Pax6 mutant cornea, and while bioinformatics comparisons revealed that 95 genes that were upregulated in PAX6 mutant corneas normally are overexpressed in the conjunctiva compared to the cornea. Similarly, corneal cytokeratins are expressed at lower levels than normal in corneas from mice heterozygous for Pax6 mutations and a total of 33 genes that normally exhibit corneal preferred expression were downregulated in the Pax6 mutant cornea compared to wildtype. L1000CDS2 analysis revealed histone deacetylase inhibitors as potential drugs capable of normalizing the mRNA transcriptome of Pax6 mutant corneas.
This analysis reveals the PAX6 mutant cornea expresses transcriptional signatures consistent with inflammation and angiogenesis. Further, transcriptome profiles are consistent with the Pax6 mutant corneal epithelium either being invaded by or transdifferentiating into, conjunctiva. Histone deacetylase inhibitors are potential drugs to reverse the corneal consequences of aniridia.
This is a 2021 ARVO Annual Meeting abstract.
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