Pathogenesis and genetic causes of keratoconus
Keratoconus is a degenerative thinning and weakening of the corneal ECM, consequent bulging of the cornea with progressive loss of vision. Affecting 1 in 1000 people, it is the second most common reason for cornea transplants worldwide. While the etiology of keratoconus is not fully understood, interactions of genetic factors with environmental stressors are suspected. Our ongoing work on keratoconus is investigating epithelial and keratocyte dysfunctions, and the altered ECMs they produce. The pathogenic cellular and ECM changes in keratoconus are increasingly thought to be due to the accumulation of multiple deleterious genetic variants in an individual. Our collaborative and interdisciplinary team is conducting whole exome and genome sequencing to identify pathogenic genetic variants in familial and isolated keratoconus.
Additionally, we are studying the transcriptomes and proteomes of corneas in keratoconus subjects undergoing corneal transplantation to identify significant regulatory signaling networks in keratoconus. We identified increased expression of stress response genes, while expression of ECM genes, NRF2-regulated antioxidant and tissue-injury response related genes were decreased in keratoconus (Shinde, 2019, Shinde, 2020). These findings are helping us to prioritize biologically significant candidate genes. Finally, we intend to use CRISPR-Cas9 gene editing approaches in cell and cornea organoid cultures to determine functional consequences of the variants we have identified. These studies will identify major genes, biomarkers and pathway that contribute to keratoconus that may be used to improve diagnoses and treatments for keratoconus.