title: Potential Modifying Loci Associated With Primary Lens Luxation, Pedal Hyperkeratosis, and Ocular Phenotypes in Miniature Bull Terriers.
abstract: OBJECTIVE
  Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs.
  
  
  METHODS
  More than 170,000 single-nucleotide polymorphisms (SNPs) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBTs, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis.
  
  
  RESULTS
  The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes.
  
  
  CONCLUSIONS
  Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani syndrome-like disease in humans as being homologous diseases.
authors.affiliation: Department of Genetic Epidemiology QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia 2School of Veterinary Science, University of Queensland, Gatton, Queensland, Australia.
authors.forename: Puya
authors.initials: P
authors.lastname: Gharahkhani
authors.affiliation: Veterinary Medical Centre, School of Veterinary Science, University of Queensland, Gatton, Queensland, Australia.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: O'Leary
authors.affiliation: Department of Genetic Epidemiology QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
authors.affiliation: School of Veterinary Science, University of Queensland, Gatton, Queensland, Australia.
authors.forename: Myat
authors.initials: M
authors.lastname: Kyaw-Tanner
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071096:ADAMTS Proteins; D000818:Animals; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D007906:Lens Subluxation / Q000235:genetics* / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype
chemical_list: D005819:Genetic Markers; D004247:DNA; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C579149:ADAMTS17 protein, human