An ADAMTS17 splice donor site mutation in dogs with primary lens luxation.
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.
Farias
Fabiana H G
FH
Department of Veterinary Pathobiology, Mason Eye Institute, Universoty of Missouri, Columbia, MO 65211, USA.
Johnson
Gary S
GS
Taylor
Jeremy F
JF
Giuliano
Elizabeth
E
Katz
Martin L
ML
Sanders
Douglas N
DN
Schnabel
Robert D
RD
McKay
Stephanie D
SD
Khan
Shahnawaz
S
Gharahkhani
Puya
P
O'Leary
Caroline A
CA
Pettitt
Louise
L
Forman
Oliver P
OP
Boursnell
Mike
M
McLaughlin
Bryan
B
Ahonen
Saija
S
Lohi
Hannes
H
Hernandez-Merino
Elena
E
Gould
David J
DJ
Sargan
David R
DR
Mellersh
Cathryn
C
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*
D022821:RNA Splice Sites; D051722:ADAM Proteins