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Two Independent Mutations in ADAMTS17 Are Associated with Primary Open Angle Glaucoma in the Basset Hound and Basset Fauve de Bretagne Breeds of Dog.

Oliver JA, Forman OP, Pettitt L, Mellersh CS - PLoS ONE (2015)

Bottom Line: Fifty clinically unaffected Basset Hounds were genotyped for this mutation and all were either heterozygous or homozygous for the wild type allele.Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 1.26 x 10-10.Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 2.80 x 10-7.

View Article: PubMed Central - PubMed

Affiliation: Department of Canine Genetics Research, Centre for Preventive Medicine, Animal Health Trust, Newmarket, Suffolk, United Kingdom.

ABSTRACT

Purpose: Mutations in ADAMTS10 (CFA20) have previously been associated with primary open angle glaucoma (POAG) in the Beagle and Norwegian Elkhound. The closely related gene, ADAMTS17, has also been associated with several different ocular phenotypes in multiple breeds of dog, including primary lens luxation and POAG. We investigated ADAMTS17 as a candidate gene for POAG in the Basset Hound and Basset Fauve de Bretagne dog breeds.

Methods: We performed ADAMTS17 exon resequencing in three Basset Hounds and three Basset Fauve de Bretagne dogs with POAG. Identified variants were genotyped in additional sample cohorts of both breeds and dogs of other breeds to confirm their association with disease.

Results: All affected Basset Hounds were homozygous for a 19 bp deletion in exon 2 that alters the reading frame and is predicted to lead to a truncated protein. Fifty clinically unaffected Basset Hounds were genotyped for this mutation and all were either heterozygous or homozygous for the wild type allele. Genotyping of 223 Basset Hounds recruited for a different study revealed a mutation frequency of 0.081 and predicted frequency of affected dogs in the population to be 0.007. Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 1.26 x 10-10. All affected Basset Fauve de Bretagne dogs were homozygous for a missense mutation in exon 11 causing a glycine to serine amino acid substitution (G519S) in the disintegrin-like domain of ADAMTS17 which is predicted to alter protein function. Unaffected Basset Fauve de Bretagne dogs were either heterozygous for the mutation (5/24) or homozygous for the wild type allele (19/24). Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 2.80 x 10-7. Genotyping of 85 dogs of unrelated breeds and 90 dogs of related breeds for this variant was negative.

Conclusion: This report documents strong associations between two independent ADAMTS17 mutations and POAG in two different dog breeds.

No MeSH data available.


Related in: MedlinePlus

Electropherograms depicting the site of the missense mutation in the Basset Fauve de Bretagne affected with POAG.The red box depicts the exact site of the mutation (CanFam3.1 chr3:40,808,345). At this location, the wild type is GG, the carrier is AG and the POAG case is GG.
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pone.0140436.g003: Electropherograms depicting the site of the missense mutation in the Basset Fauve de Bretagne affected with POAG.The red box depicts the exact site of the mutation (CanFam3.1 chr3:40,808,345). At this location, the wild type is GG, the carrier is AG and the POAG case is GG.

Mentions: Visual scanning of the sequence read alignments from clinically affected Basset Fauve de Bretagne dogs revealed only one variant that segregated with disease—a homozygous G>A substitution in exon 11 of ADAMTS17 (CanFam3.1 chr3:40,808,345, Fig 3). All affected Basset Fauve de Bretagne dogs were homozygous for this non-synonymous SNP which causes a glycine to serine (G519S) amino acid change in the disintegrin-like domain of ADAMTS17 and is predicted to be deleterious by SIFT [30]. Sequencing of 24 clinically unaffected Basset Fauve de Bretagne dogs revealed five were heterozygous for the mutation and 19 were homozygous for the wild type allele. The association statistic of the variant with POAG based on the entire genotyping dataset was p = 2.80 x 10−7. Genotyping of 85 dogs of unrelated breeds (mixed breed panel) and 90 dogs of related breeds (Basset Hound, Wire Haired Dachshund, Petit Basset Griffon Vendeen, Grande Basset Griffon Vendeen) for this variant with a TaqMan allelic assay revealed them all to be homozygous for the wild type allele.


Two Independent Mutations in ADAMTS17 Are Associated with Primary Open Angle Glaucoma in the Basset Hound and Basset Fauve de Bretagne Breeds of Dog.

Oliver JA, Forman OP, Pettitt L, Mellersh CS - PLoS ONE (2015)

Electropherograms depicting the site of the missense mutation in the Basset Fauve de Bretagne affected with POAG.The red box depicts the exact site of the mutation (CanFam3.1 chr3:40,808,345). At this location, the wild type is GG, the carrier is AG and the POAG case is GG.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608710&req=5

pone.0140436.g003: Electropherograms depicting the site of the missense mutation in the Basset Fauve de Bretagne affected with POAG.The red box depicts the exact site of the mutation (CanFam3.1 chr3:40,808,345). At this location, the wild type is GG, the carrier is AG and the POAG case is GG.
Mentions: Visual scanning of the sequence read alignments from clinically affected Basset Fauve de Bretagne dogs revealed only one variant that segregated with disease—a homozygous G>A substitution in exon 11 of ADAMTS17 (CanFam3.1 chr3:40,808,345, Fig 3). All affected Basset Fauve de Bretagne dogs were homozygous for this non-synonymous SNP which causes a glycine to serine (G519S) amino acid change in the disintegrin-like domain of ADAMTS17 and is predicted to be deleterious by SIFT [30]. Sequencing of 24 clinically unaffected Basset Fauve de Bretagne dogs revealed five were heterozygous for the mutation and 19 were homozygous for the wild type allele. The association statistic of the variant with POAG based on the entire genotyping dataset was p = 2.80 x 10−7. Genotyping of 85 dogs of unrelated breeds (mixed breed panel) and 90 dogs of related breeds (Basset Hound, Wire Haired Dachshund, Petit Basset Griffon Vendeen, Grande Basset Griffon Vendeen) for this variant with a TaqMan allelic assay revealed them all to be homozygous for the wild type allele.

Bottom Line: Fifty clinically unaffected Basset Hounds were genotyped for this mutation and all were either heterozygous or homozygous for the wild type allele.Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 1.26 x 10-10.Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 2.80 x 10-7.

View Article: PubMed Central - PubMed

Affiliation: Department of Canine Genetics Research, Centre for Preventive Medicine, Animal Health Trust, Newmarket, Suffolk, United Kingdom.

ABSTRACT

Purpose: Mutations in ADAMTS10 (CFA20) have previously been associated with primary open angle glaucoma (POAG) in the Beagle and Norwegian Elkhound. The closely related gene, ADAMTS17, has also been associated with several different ocular phenotypes in multiple breeds of dog, including primary lens luxation and POAG. We investigated ADAMTS17 as a candidate gene for POAG in the Basset Hound and Basset Fauve de Bretagne dog breeds.

Methods: We performed ADAMTS17 exon resequencing in three Basset Hounds and three Basset Fauve de Bretagne dogs with POAG. Identified variants were genotyped in additional sample cohorts of both breeds and dogs of other breeds to confirm their association with disease.

Results: All affected Basset Hounds were homozygous for a 19 bp deletion in exon 2 that alters the reading frame and is predicted to lead to a truncated protein. Fifty clinically unaffected Basset Hounds were genotyped for this mutation and all were either heterozygous or homozygous for the wild type allele. Genotyping of 223 Basset Hounds recruited for a different study revealed a mutation frequency of 0.081 and predicted frequency of affected dogs in the population to be 0.007. Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 1.26 x 10-10. All affected Basset Fauve de Bretagne dogs were homozygous for a missense mutation in exon 11 causing a glycine to serine amino acid substitution (G519S) in the disintegrin-like domain of ADAMTS17 which is predicted to alter protein function. Unaffected Basset Fauve de Bretagne dogs were either heterozygous for the mutation (5/24) or homozygous for the wild type allele (19/24). Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 2.80 x 10-7. Genotyping of 85 dogs of unrelated breeds and 90 dogs of related breeds for this variant was negative.

Conclusion: This report documents strong associations between two independent ADAMTS17 mutations and POAG in two different dog breeds.

No MeSH data available.


Related in: MedlinePlus