Abstract
Abstract: :
Purpose: Keratoconus (KC) is a non–inflammatory thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and altered visual acuity. Although both genetic and non–genetic factors have been associated with KC, its molecular basis is still elusive. We identified an Ecuadorian cohort in which KC without other ocular or systemic features is transmitted as an autosomal dominant trait with incomplete penetrance. Here we present the results of sequencing and linkage analyzes which were performed to verify the association between KC in these families and one or more of the previously reported KC loci. Methods: To date, we have examined, collected blood, and purified DNA from 148 individuals from 22 multiplex families with KC. Subjects were diagnosed clinically with KC by slit lamp examination and corneal topography. Linkage analyzes and sequencing were performed. Results: We excluded previously assigned KC loci on chromosomes 3, 15, 16, and 20 by linkage analysis and initiated a genome–wide screen for a KC locus. We genotyped 148 individuals with fluorescent markers with an average spacing of 10 cM spanning chromosomes 1, 2, 3, 4, 14, 15, 16, 17, 18, 19, 20, 21, and 22. Additionally, the coding exons of VSX1 in 18 individuals from the Ecuadorian families (1 individual from each family with multiple affected individuals) and 2 ethnically matched control individuals (Ecuadorian individuals with no ocular abnormalities) were sequenced. Three single nucleotide polymorphisms (SNPs) in the VSX1 coding region (18G→T, 174G→T and 542A→G) were identified, but no mutation was found in the gene. Conclusions: Keratoconus in our families is not linked to any of the previously defined KC loci. We excluded VSX1 as a candidate for KC in this population by sequencing. No evidence for linkage between KC and analyzed markers was observed. A genome–wide screen is in progress.
Keywords: keratoconus • linkage analysis