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R. C. Vo, V. S. Yellore, M. A. Khan, M. R. Damani, S. A. Rayner, D. S. Fubara, B. Saravanabavanandhan, K. M. Kamal, A. J. Aldave; A Strategy to Identify the Genetic Basis of Keratoconus Using a Candidate Gene Approach Incorporating Gene Expression and Linkage Analysis Data. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1005.
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© ARVO (1962-2015); The Authors (2016-present)
To describe a strategy to identify the genetic basis of keratoconus using a candidate gene approach incorporating linkage analysis and gene expression data.
Genes mapped to chromosomal loci to which keratoconus has been linked were identified as positional candidate genes. Publicly available databases were examined to determine which positional candidate genes were expressed in normal and/or keratoconic corneas. The functions of the expressed positional candidate genes were then evaluated to prioritize the genes for screening. Direct sequencing of the selected functional and positional candidate genes was performed in 50 unrelated individuals with clinical and topographic evidence of keratoconus.
Keratoconus has been mapped to loci on 9 different chromosomes: 2, 3, 5, 6, 9, 15, 16, 17 and 20. However, the loci that were mapped to chromosomes 6, 15, and 17 were not investigated as the families demonstrated keratoconus in association with other ocular disorders not found in the affected individuals that were screened. The number of positional candidate genes found to be expressed in either normal or keratoconic corneas for each of the remaining 6 chromosomal loci was (chromosome - # of candidate genes): 2 - 4; 3 - 25; 5 - 3; 9 - 3; 16 - 9; and 20-10. Four positional and functional candidate genes were initially selected for screening: WDR35 (2p24.1), SDC1 (2p24.1), GLRX (5q14), and SLPI (20q12). Seven known SNPs were identified in the selected genes, in addition to three novel variants in SDC1 and five novel variants in WDR35. Two of the three novel sequence variants in SDC1 and one of the four novel sequence variants in WDR35 were identified in control individuals, indicating that they were non-pathogenic polymorphisms. The other novel sequence variant in SDC1 was identified in an unaffected relative of the affected proband, also indicating that it was not associated with the development of keratoconus. Control samples are currently being screened for the other four novel sequence variants in WDR35,which will also be screened for in relatives of the affected individuals if not identified in controls.
We have identified positional and functional candidate genes for keratoconus using publicly available databases. The screening of these candidate genes in a large number of unrelated keratoconus probands will hopefully provide insight into the genetic basis of this common corneal degeneration.
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