Dataset Information

Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma.

ABSTRACT:

Background

In humans, ADAMTS17 mutations are known to cause Weill-Marchesani-like syndrome, which is characterised by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Breed-specific homozygous mutations in ADAMTS17 are associated with primary open angle glaucoma (POAG) in several dog breeds, including the Petit Basset Griffon Vendeen (PBGV) and Shar Pei (SP). We hypothesised that these mutations are associated with short stature in these breeds.

Methods

Two hundred thirty-three PBGV and 66 SP were genotyped for their breed-specific ADAMTS17 mutations. The height of each dog was measured at the withers. We used linear (per allele) regression to assess the association between ADAMTS17 mutations and height as a continuous variable, and linear regression and likelihood ratio tests to assess the shape of the association by comparing a general model with a linear (per allele) model.

Results

The adjusted mean heights of affected, carrier, and clear PBGV were 33.49?cm (n =?21, 95% CI 32.78-34.19?cm), 34.88?cm (n =?85, 95% CI 34.53-35.25?cm), and 34.92?cm (n =?121, 95% CI 34.62-35.21?cm), respectively. The mean heights of affected, carrier, and clear SP were 43.96?cm (n =?9, 95% CI 41.88-46.03?cm), 47.56?cm (n =?28, 95% CI 45.50-48.63?cm), and 48.95?cm (n =?23, 95% CI 47.80-50.11?cm), respectively. There was a significant difference between the height of affected and clear animals in the PBGV (P =?0.001) and the SP (P =?ConclusionsADAMTS17 POAG mutations are significantly associated with height in these breeds.

SUBMITTER: Jeanes EC

PROVIDER: S-EPMC6524303 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Glaucoma-causing <i>ADAMTS17</i> mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma.

Jeanes Emily C EC Oliver James A C JAC Ricketts Sally L SL Gould David J DJ Mellersh Cathryn S CS

Canine genetics and epidemiology 20190517

<h4>Background</h4>In humans, <i>ADAMTS17</i> mutations are known to cause Weill-Marchesani-like syndrome, which is characterised by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Breed-specific homozygous mutations in <i>ADAMTS17</i> are associated with primary open angle glaucoma (POAG) in several dog breeds, including the Petit Basset Griffon Vendeen (PBGV) and Shar Pei (SP). We hypothesised that these mutations are associated with short stature in these breeds. ...[more]

PMID: 31131111

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Project description:PurposeMutations 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.MethodsWe 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.ResultsAll 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.ConclusionThis report documents strong associations between two independent ADAMTS17 mutations and POAG in two different dog breeds.