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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

Next generation and Sanger sequencing results depicting the site of 19bp deletion in the Basset Hound with POAG.a) IGV view of the 19 bp deletion in a Basset Hound affected with POAG. The location of this homozygous deletion is chr3:40,614,853–40,614,872 (CanFam3.1). b) Electropherograms depicting the site of the deletion. The red box delineates the affected sequence in wild type, carrier and POAG-affected dogs.
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pone.0140436.g001: Next generation and Sanger sequencing results depicting the site of 19bp deletion in the Basset Hound with POAG.a) IGV view of the 19 bp deletion in a Basset Hound affected with POAG. The location of this homozygous deletion is chr3:40,614,853–40,614,872 (CanFam3.1). b) Electropherograms depicting the site of the deletion. The red box delineates the affected sequence in wild type, carrier and POAG-affected dogs.

Mentions: Visual scanning of the sequence read alignments from clinically affected Basset Hounds revealed only one variant that segregated with disease in the three affected dogs. This variant was a homozygous 19 bp deletion in exon 2 of ADAMTS17 (CanFam3.1 chr3:40,614,853–40,614,872, Fig 1a) and was confirmed by Sanger sequencing (Fig 1b). The deletion is predicted to alter the reading frame of the gene, leading to 87 aberrant amino acids before introducing a premature stop codon at the 5’ end of exon 3, a predicted truncation of 86.1% of the protein (Fig 2). Fifty clinically unaffected Basset Hounds over the age of 72 months (controls) were genotyped for this allele; all were homozygous for the wild type. Genotyping of 173 additional Basset Hounds recruited for a different study and also known to be free of clinical signs of POAG, revealed 137 were homozygous for the wild type allele and 36 were heterozygous for the mutation. The frequency of the deletion in this subset of 223 Basset hounds was therefore 0.081 and the predicted frequency of affected dogs in the population estimated to be 0.007. One hundred and fifty two dogs of unrelated breeds (mixed breed panel) were all homozygous for the wild type allele. Following identification of this mutation, the owners of all affected dogs were contacted and pedigrees were obtained and reviewed. Analysis of these revealed two of the affected dogs to be full siblings although the third affected dog shared no common ancestors in its five generation pedigree. Taking into account the presence of the two full siblings, the association statistic between the deletion and POAG based on the entire genotyping dataset was p = 1.26 x 10−10.


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)

Next generation and Sanger sequencing results depicting the site of 19bp deletion in the Basset Hound with POAG.a) IGV view of the 19 bp deletion in a Basset Hound affected with POAG. The location of this homozygous deletion is chr3:40,614,853–40,614,872 (CanFam3.1). b) Electropherograms depicting the site of the deletion. The red box delineates the affected sequence in wild type, carrier and POAG-affected dogs.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140436.g001: Next generation and Sanger sequencing results depicting the site of 19bp deletion in the Basset Hound with POAG.a) IGV view of the 19 bp deletion in a Basset Hound affected with POAG. The location of this homozygous deletion is chr3:40,614,853–40,614,872 (CanFam3.1). b) Electropherograms depicting the site of the deletion. The red box delineates the affected sequence in wild type, carrier and POAG-affected dogs.
Mentions: Visual scanning of the sequence read alignments from clinically affected Basset Hounds revealed only one variant that segregated with disease in the three affected dogs. This variant was a homozygous 19 bp deletion in exon 2 of ADAMTS17 (CanFam3.1 chr3:40,614,853–40,614,872, Fig 1a) and was confirmed by Sanger sequencing (Fig 1b). The deletion is predicted to alter the reading frame of the gene, leading to 87 aberrant amino acids before introducing a premature stop codon at the 5’ end of exon 3, a predicted truncation of 86.1% of the protein (Fig 2). Fifty clinically unaffected Basset Hounds over the age of 72 months (controls) were genotyped for this allele; all were homozygous for the wild type. Genotyping of 173 additional Basset Hounds recruited for a different study and also known to be free of clinical signs of POAG, revealed 137 were homozygous for the wild type allele and 36 were heterozygous for the mutation. The frequency of the deletion in this subset of 223 Basset hounds was therefore 0.081 and the predicted frequency of affected dogs in the population estimated to be 0.007. One hundred and fifty two dogs of unrelated breeds (mixed breed panel) were all homozygous for the wild type allele. Following identification of this mutation, the owners of all affected dogs were contacted and pedigrees were obtained and reviewed. Analysis of these revealed two of the affected dogs to be full siblings although the third affected dog shared no common ancestors in its five generation pedigree. Taking into account the presence of the two full siblings, the association statistic between the deletion and POAG based on the entire genotyping dataset was p = 1.26 x 10−10.

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