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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

A selected region of the amino acid sequence of the disintegrin-like domain in the entire ADAMTS family.The region is centred on the glycine residue (in red) which is highly conserved and is the site of the missense mutation in the Basset Fauve de Bretagne.
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pone.0140436.g005: A selected region of the amino acid sequence of the disintegrin-like domain in the entire ADAMTS family.The region is centred on the glycine residue (in red) which is highly conserved and is the site of the missense mutation in the Basset Fauve de Bretagne.

Mentions: The variant we have identified that is associated with POAG in the Basset Fauve de Bretagne is a non-synonymous SNP that results in a glycine to serine amino acid change in the disintegrin-like domain of the protein which is essential for the catalytic function of the protein [31] (Fig 4). Glycine is a highly conserved residue within the disintegrin-like domain across the entire ADAMTS family and also across species (Figs 5 and 6), providing strong evidence that this SNP is causal for POAG in this breed. Furthermore, 85 dogs of unrelated breeds and 90 dogs of related breeds were all homozygous for the wild type allele indicating that this variant is not a common polymorphism within the wider canine population.


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)

A selected region of the amino acid sequence of the disintegrin-like domain in the entire ADAMTS family.The region is centred on the glycine residue (in red) which is highly conserved and is the site of the missense mutation in the Basset Fauve de Bretagne.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140436.g005: A selected region of the amino acid sequence of the disintegrin-like domain in the entire ADAMTS family.The region is centred on the glycine residue (in red) which is highly conserved and is the site of the missense mutation in the Basset Fauve de Bretagne.
Mentions: The variant we have identified that is associated with POAG in the Basset Fauve de Bretagne is a non-synonymous SNP that results in a glycine to serine amino acid change in the disintegrin-like domain of the protein which is essential for the catalytic function of the protein [31] (Fig 4). Glycine is a highly conserved residue within the disintegrin-like domain across the entire ADAMTS family and also across species (Figs 5 and 6), providing strong evidence that this SNP is causal for POAG in this breed. Furthermore, 85 dogs of unrelated breeds and 90 dogs of related breeds were all homozygous for the wild type allele indicating that this variant is not a common polymorphism within the wider canine population.

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