title: An ADAMTS17 splice donor site mutation in dogs with primary lens luxation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Veterinary Pathobiology, Mason Eye Institute, Universoty of Missouri, Columbia, MO 65211, USA.
authors.forename: Fabiana H G
authors.initials: FH
authors.lastname: Farias
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Giuliano
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Sanders
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schnabel
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: McKay
authors.forename: Shahnawaz
authors.initials: S
authors.lastname: Khan
authors.forename: Puya
authors.initials: P
authors.lastname: Gharahkhani
authors.forename: Caroline A
authors.initials: CA
authors.lastname: O'Leary
authors.forename: Louise
authors.initials: L
authors.lastname: Pettitt
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Forman
authors.forename: Mike
authors.initials: M
authors.lastname: Boursnell
authors.forename: Bryan
authors.initials: B
authors.lastname: McLaughlin
authors.forename: Saija
authors.initials: S
authors.lastname: Ahonen
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Elena
authors.initials: E
authors.lastname: Hernandez-Merino
authors.forename: David J
authors.initials: DJ
authors.lastname: Gould
authors.forename: David R
authors.initials: DR
authors.lastname: Sargan
authors.forename: Cathryn
authors.initials: C
authors.lastname: Mellersh
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007906:Lens Subluxation / Q000235:genetics* / Q000662:veterinary*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics; D056846:Weill-Marchesani Syndrome / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D051722:ADAM Proteins