An ADAMTS17 Splice Donor Site Mutation in Dogs with Primary Lens Luxation

作者:Farias Fabiana H G; Johnson Gary S*; Taylor Jeremy F; Giuliano Elizabeth; Katz Martin L; Sanders Douglas N; Schnabel Robert D; McKay Stephanie D; Khan Shahnawaz; Gharahkhani Puya; O'Leary Caroline A; Pettitt Louise; Forman Oliver P; Boursnell Mike; McLaughlin Bryan; Ahonen Saija; Lohi Hannes; Hernandez Merino Elena; Gould David J; Sargan David R; Mellersh Cathryn
来源:Investigative Ophthalmology & Visual Science, 2010, 51(9): 4716-4721.
DOI:10.1167/iovs.09-5142

摘要

PURPOSE. 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.
METHODS. 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.
RESULTS. 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.
CONCLUSIONS. 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. (Invest Ophthalmol Vis Sci. 2010; 51: 4716-4721) DOI: 10.1167/iovs.09-5142

  • 出版日期2010-9