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Fabiana H. G. Farias, Gary S. Johnson, Jeremy F. Taylor, Elizabeth Giuliano, Martin L. Katz, Douglas N. Sanders, Robert D. Schnabel, Stephanie D. McKay, Shahnawaz Khan, Puya Gharahkhani, Caroline A. O'Leary, Louise Pettitt, Oliver P. Forman, Mike Boursnell, Bryan McLaughlin, Saija Ahonen, Hannes Lohi, Elena Hernandez-Merino, David J. Gould, David R. Sargan, Cathryn Mellersh; An ADAMTS17 Splice Donor Site Mutation in Dogs with Primary Lens Luxation. Invest. Ophthalmol. Vis. Sci. 2010;51(9):4716-4721. doi: https://doi.org/10.1167/iovs.09-5142.
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To identify the genetic cause of isolated canine ectopia lentis, a well-characterized veterinary disease commonly referred to as primary lens luxation (PLL) and to compare the canine disease with a newly described human Weill-Marchesani syndrome (WMS)–like disease of similar genetic etiology.
Genomewide association analysis and fine mapping by homozygosity were used to identify the chromosomal segment harboring the PLL locus. The resequencing of a regional candidate gene was used to discover a mutation in a splice donor site predicted to cause exon skipping. Exon skipping was confirmed by reverse transcription-polymerase chain reaction amplification of RNA isolated from PLL-affected eyes and from skin fibroblast cultures from PLL-affected dogs. An allelic discrimination assay was used to genotype individual dogs at the splice donor site mutation.
The PLL locus was mapped to a 664-kb region of canine chromosome 3 containing regional candidate gene ADAMTS17. Resequencing ADAMTS17 revealed a GT→AT splice-donor-site mutation at the 5′ end of intron 10. The predicted exon 10 skipping and resultant frame shift were confirmed with RNA derived from PLL-affected dogs. The ADAMTS17 mutation was significantly associated with clinical PLL in three different dog breeds.
A truncating mutation in canine ADAMTS17 causes PLL, a well-characterized veterinary disease, which can now be compared to a recently described rare WMS-like disease caused by truncating mutations of the human ADAMTS17 ortholog.
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