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Dina Ahram, Sinisa D Grozdanic, Arjen Henkes, Rob W Collin, Markus H Kuehn; Genetic Mapping of a Novel Disease Locus in a Canine Model of Primary Angle Closure Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3798.
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Primary angle-closure glaucoma (PACG) is one of the most prevalent forms of glaucoma. Several dog breeds are susceptible to developing PACG, which suggests a genetic basis of the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG causing sequence variants using the dog as a model organism.
Extensive clinical phenotyping of all pedigree members was conducted. 170,000 SNP markers were genotyped in 9 affected and 12 unaffected pedigree members using the Illumina CanineHD SNP Chip. Two-point and multipoint linkage analyses were performed using Superlink-Online SNP-1.1. To identify homozygous regions that segregate with the disease phenotype in the affected animals, homozygosity mapping was carried out using Homozygosity Mapper. Targeted exome capture was performed using the Agilent SureSelect exon kit and sequence alignment was executed on CanFam2 Ensemble and Refseq reference sequences.
Using multipoint linkage analysis a 1.82Mbp locus was mapped to the distal portion of chromosome 19 (Chr19:54,949,124-56,765,346) with a maximum LOD score of 3.24. The locus contains 12 predicted canine genes and is completely syntenic to a human locus on chromosome 2. Investigation of haplotype phase revealed complete concordance of haploblock inheritance with the disease phenotype in all affected Bassets. Homozygosity mapping revealed sharing of a shared 0.49 Mbp region within the mapped haploblock among all affected versus unaffected animals. Using exome sequencing analysis, a total of 109 variants segregating in a recessive pattern were identified. Of the disease-segregating variants, 25 were found within exons and 4 of these resulted in amino acid substitutions.
Our findings of a genetically linked locus support the segregation of an underlying genetic defect with PACG in the Basset Hound. Our results also provide evidence for a number of potentially causative variants that segregate with PACG in the BH, which are currently the focus of investigation. We anticipate for these studies to provide valuable insight into the genetics of PACG by enabling the identification of genes and mechanisms that contribute to the development of disease in both canines and humans.
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