Genetic variants of LAMC1, ATP1B1 as risk factors and transcriptional regulation of CASP8AP2 in the pathophysiology of Fuchs Endothelial Corneal Dystrophy

Abstract

Fuchs Endothelial Corneal dystrophy (FECD, OMIM # 136800) is an age-related, progressive, bilateral and, multifactorial dystrophy. It is marked by the reduction in the number of corneal endothelial cells, the fibroblastic transformation of remaining endothelium cells and deposition of the excess extracellular matrix proteins in the Descemet’s membrane (DM). All of these molecular pathomechanism ultimately lead to the cloudiness in the cornea, loss of visual acuity, and formation of the painful tiny blisters on the surface of the cornea. FECD is categorized into two types: early and late, depending on when the symptoms begin to appear. Additionally, cases of FECD occur more frequently in women than in men. Researchers have identified various mutations and polymorphisms that are genetically associated with the pathophysiology of this disease in various populations. Previously we have also identified different polymorphisms associated with the FECD in the Indian population. But the genetic load of these polymorphisms are low compared to the Caucasian population hinting at the association of other new variants with FECD in our population. In the past, researchers observed that caspase 8 associated protein 2 (CASP8AP2) promotes epithelial to mesenchymal (EMT) transition by protecting Zinc finger E-box-binding homeobox 1 (ZEB1) from E3 ubiquitin ligases. Because ZEB1 is also overexpressed in the FECD corneal endothelium, so we hypothesized that upregulation of CASP8AP2 may cause the overexpression of ZEB1 in the FECD condition. Also, the molecular mechanism of the transcriptional regulation of CASP8AP2 is not yet studied. The focus of this present study is to identify the genetic and functional association of novel polymorphisms associated with FECD in the Indian population and transcriptional regulation of CASP8AP2 related with the pathophysiology of FECD.