The D144E substitution in the VSX1 gene: a non-pathogenic variant or a disease causing mutation?

Purpose: To identify the genetic defect associated with keratoconus (KC) in an Ashkenazi Jewish family and to evaluate its nature and its phenotypic expression within carriers.
Methods: A three generation Ashkenazi Jewish family with KC was ascertained. Diagnosis was based on clinical examination and corneal topography. Segregation analysis was performed using micro-satellite polymorphic markers in close proximity to 7 previously associated KC loci and genes. Mutation analysis of the VSX1 gene was performed by direct sequencing of PCR-amplified exons, and a BseR1 restriction assay. In selected cases, where the genotype was consistent with KC, additional effort to detect subtle corneal changes was made by computerized Orbscan measurements.
Results: We found co-segregation between the KC phenotype and a polymorphic marker close to the VSX1. Sequencing revealed a previously described missense mutation (D144E). All of the mutation carriers manifested pathologic corneal findings; some had overt KC while others had subtle corneal alterations identifiable only by Orbscan.
Conclusions: These findings support the pathogenic role of VSX1 gene in KC. The variable expression among the carriers, suggests the involvement of other factors in determining the final phenotype.