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Michelle J. Kim, Isabella N. Lai, Catherine K. Nguyen, Sylvia A. Rayner, Vivek S. Yellore, Anthony J. Aldave; Exclusion of Pathogenic Coding Region Mutations in Positional Candidate Genes for Posterior Amorphous Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1103.
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© ARVO (1962-2015); The Authors (2016-present)
Posterior amorphous corneal dystrophy (PACD) is classified as an autosomal dominant dystrophy, but is associated with a constellation of features consistent with an anterior segment dysgenesis, including posterior lamellar corneal opacification, corneal thinning and flattening, peripheral corneal scleralization, iridocorneal adhesions, correctopia, and iris atrophy. Genome-wide linkage analysis has demonstrated linkage to chromosome region 12q21.33. Twenty-two genes have been mapped to the linked interval; sequencing of the coding regions of four of the positional candidate genes did not reveal a pathogenic mutation. The purpose of this project was to screen the coding regions of the remaining 18 genes to identify the genetic basis of PACD.
PCR amplification of the exonic regions of the previously unscreened 18 positional candidate genes was performed using DNA from two unaffected and two affected members of a previously reported PACD family and an unrelated, unaffected control individual. Automated sequencing was performed, and sequence variants were identified by comparing the generated and wild type sequences.
Thirty nine sequence variants were identified in 11 of the 18 genes, including 36 previously identified and 3 novel variants, of which 18 were non-coding RNA changes, 10 were silent mutations, 9 were missense mutations, 1 was a nonsense mutation, and 1 was a deletion. None of the identified sequence variants segregated with the affected phenotype in the family.
Screening of the coding regions of the positional candidate genes for PACD has not revealed the pathogenic mutation in the family in which linkage to chromosome region 12q21.33 was demonstrated. The pathogenic mutation may involve a copy number variant, be in a non-coding region of one of the genes already screened, or be located outside the linkage interval. To investigate these possibilities, large scale resequencing of the PACD linked interval and screening of the genes located adjacent to the linked interval are planned.
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