Limits...
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

ADAMTS17 protein structure denoting amino acid positions of the Basset Hound and Basset Fauve de Bretagne POAG mutations.ADAMTS17 is composed of a signal peptide (SP), prodomain (PRO), catalytic domain (CAT) (composed of the metalloproteinase (MP) and disintegrin-like domains (DL)) and an ancillary domain (ANC). The Basset Hound deletion corresponds to amino acid position 65 which is located in PRO. The Basset Fauve de Bretagne mutation corresponds to amino acid position 519 which is located in DL. Adapted from Kelwick et al. [31]
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608710&req=5

pone.0140436.g004: ADAMTS17 protein structure denoting amino acid positions of the Basset Hound and Basset Fauve de Bretagne POAG mutations.ADAMTS17 is composed of a signal peptide (SP), prodomain (PRO), catalytic domain (CAT) (composed of the metalloproteinase (MP) and disintegrin-like domains (DL)) and an ancillary domain (ANC). The Basset Hound deletion corresponds to amino acid position 65 which is located in PRO. The Basset Fauve de Bretagne mutation corresponds to amino acid position 519 which is located in DL. Adapted from Kelwick et al. [31]

Mentions: In the Basset Hound, a homozygous 19 bp deletion in exon 2 was present in all POAG-affected dogs. The deletion is predicted to alter the reading frame of the transcript and introduce a premature stop codon at the 5’ end of exon 3, which would result in a truncated and aberrant protein if the RNA is stable and not subjected to nonsense-mediated decay (Fig 2). If the transcript is translated the protein is expected to be truncated by 86.1% which would include the entire catalytic domain which is expected to lead to complete loss of protein function (Fig 4). Further supportive evidence for the deletion as the causative mutation of POAG in the Basset Hound was derived from genotyping. Our genotyping cohort included 223 Basset Hounds which had undergone complete ophthalmic examination and were found to be free from clinical signs of POAG at the time. 50 of these were significantly older than the POAG cases and were thought to be at very low risk of developing POAG in the future. These dogs served as controls and none were found to be homozygous for the identified mutation. Genotyping of the entire cohort allowed calculation of carrier frequency within the breed within the United Kingdom. These dogs were all resident and distributed widely around the United Kingdom and DNA had been collected from them for a parallel study. They can therefore be considered a random cohort with respect to the current study and representative of the Basset Hound population in the UK. The frequency of the mutant allele (0.081) and expected frequency of dogs affected with POAG (0.007) are fairly high. These data, together with the fact that POAG is a painful and blinding condition, underpin the importance of this mutation. With this in mind, a DNA test has been developed to allow Basset Hound breeders to genotype their dogs prior to breeding.


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)

ADAMTS17 protein structure denoting amino acid positions of the Basset Hound and Basset Fauve de Bretagne POAG mutations.ADAMTS17 is composed of a signal peptide (SP), prodomain (PRO), catalytic domain (CAT) (composed of the metalloproteinase (MP) and disintegrin-like domains (DL)) and an ancillary domain (ANC). The Basset Hound deletion corresponds to amino acid position 65 which is located in PRO. The Basset Fauve de Bretagne mutation corresponds to amino acid position 519 which is located in DL. Adapted from Kelwick et al. [31]
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140436.g004: ADAMTS17 protein structure denoting amino acid positions of the Basset Hound and Basset Fauve de Bretagne POAG mutations.ADAMTS17 is composed of a signal peptide (SP), prodomain (PRO), catalytic domain (CAT) (composed of the metalloproteinase (MP) and disintegrin-like domains (DL)) and an ancillary domain (ANC). The Basset Hound deletion corresponds to amino acid position 65 which is located in PRO. The Basset Fauve de Bretagne mutation corresponds to amino acid position 519 which is located in DL. Adapted from Kelwick et al. [31]
Mentions: In the Basset Hound, a homozygous 19 bp deletion in exon 2 was present in all POAG-affected dogs. The deletion is predicted to alter the reading frame of the transcript and introduce a premature stop codon at the 5’ end of exon 3, which would result in a truncated and aberrant protein if the RNA is stable and not subjected to nonsense-mediated decay (Fig 2). If the transcript is translated the protein is expected to be truncated by 86.1% which would include the entire catalytic domain which is expected to lead to complete loss of protein function (Fig 4). Further supportive evidence for the deletion as the causative mutation of POAG in the Basset Hound was derived from genotyping. Our genotyping cohort included 223 Basset Hounds which had undergone complete ophthalmic examination and were found to be free from clinical signs of POAG at the time. 50 of these were significantly older than the POAG cases and were thought to be at very low risk of developing POAG in the future. These dogs served as controls and none were found to be homozygous for the identified mutation. Genotyping of the entire cohort allowed calculation of carrier frequency within the breed within the United Kingdom. These dogs were all resident and distributed widely around the United Kingdom and DNA had been collected from them for a parallel study. They can therefore be considered a random cohort with respect to the current study and representative of the Basset Hound population in the UK. The frequency of the mutant allele (0.081) and expected frequency of dogs affected with POAG (0.007) are fairly high. These data, together with the fact that POAG is a painful and blinding condition, underpin the importance of this mutation. With this in mind, a DNA test has been developed to allow Basset Hound breeders to genotype their dogs prior to breeding.

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