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N. M. Ellinwood, K. H. Deckman, Z. Zhao, M. M. Rutz-Mendicino, J. K. Jens, V. A. David, M. H. Kuehn, S. J. O'Brien, M. A. Menotti-Raymond, G. J. McLellan; Candidate Gene Analysis of a Feline Model of Primary Congenital Glaucoma Implicates LTBP2 as the Causative Locus. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6390.
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© ARVO (1962-2015); The Authors (2016-present)
We previously described a large eyed model of primary congenital glaucoma (PCG) in Siamese cats. The model exists as a research breeding colony. Breeding studies demonstrated the condition is a fully penetrant autosomal recessive trait. It is independent of potentially confounding phenotypes, including coat color. Families were produced with an aim of conducting a linkage analysis to identify the causative locus
We adopted a candidate gene approach for screening the pedigree using short tandem repeat loci (STRs), selected from the domestic cat genome browser GARField (http://lgd.abcc.ncifcrf.gov/cgi-bin/gbrowse/cat/), and tightly linked to 8 candidate genes previously reported to be mutated/linked to autosomal recessively inherited PGC in humans (MYOC, FOXC1, CYP1B1, PITX2, OPTN, SH3PXD2B, LTBP2, and PAX6). Amplification of the STRs was performed by a touchdown PCR reaction protocol. PCR products were fluorescently labeled using M13 tailed primers. Products were analyzed on an Applied Biosystems Model 3100 genetic analyzer with Genescan version 3.7 and Genotyper version 2.5 software. Linkage analysis computations were performed with SUPERLINK (http://bioinfo.cs.technion.ac.il/superlink-online/). We modeled PCG as a fully penetrant, AR disease with disease allele frequency of 0.001. Marker allele frequencies were set as equal.
In a preliminary screening of individuals from the pedigree, all loci except the recently described LTBP2 gene were excluded due to lack of association between the affected founders’ and progenies’ genotypes and phenotypes. The recently described locus, LTBP2 did show an association with the PCG affected phenotype, and full pedigree linkage yielded a LOD score of 18.08 with zero recombination.
The identification of LTBP2 as the putative gene responsible for feline PCG greatly increases the value and utility of this model as a tool for the glaucoma research community, as it demonstrates this model to likely be a fully authentic homologue to a human form of PCG. Furthermore it will aid in the development of this model through by focusing efforts on the full characterization of the mutation, studies in pathogenesis, and evaluations of potential therapies.
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