Southern Dandie Dinmont Terrier Club

 

Glaucoma is among the leading causes of blindness both in humans and in dogs. Glaucoma is defined by elevation of the intraocular pressure. Glaucoma can be hereditary or secondary due to some other ocular disease. Using a genome-wide mapping approach with canine-specific markers we have identified a novel glaucoma locus to CFA8 in Dandie Dinmont Terrier dog breed (DDT) with a late-onset disease. The overall associated region is large covering about 10 Mb of sequence but fine-mapping narrows the best haplotype to a 2 Mb critical region. Our ongoing re-sequencing efforts of the entire locus aim to identify the causative mutation, which may help us to understand the genetic background of glaucoma across species. The identified locus maps to a syntetic region previously associated with human glaucoma too.

Glaucoma in DDTs

Glaucoma is a painful disease with an increased intraocular pressure (IOP) that damages the optic nerve and causes loss of retinal ganglion cells. Damage in the optic nerve is permanent leading to irreversible loss of vision. The development of primary glaucoma is hereditary and caused by genetic factors. Glaucoma can also be secondary occurring as a result of some other cause. The development of glaucoma is related to structural abnormalities associated with the drainage or iridocorneal angle including pectinate ligament dysplasia.

Based on the gonioscopy results available from 26 out of 33 affected dogs in our study, primary glaucoma in DDTs develops slowly, affecting middle-aged and elderly dogs with an average age of onset at 7.07 years. The affected dogs had elevated IOP 25-42 mmHg (normal 15-25 mmHg). Gonioscopy revealed fibrae latae (broadened and abnormal) and laminae (thinned) changes in the pectinate ligaments and the affected dogs had narrowed or closed iridocorneal angles.

Genetic studies and results

With the help of the DDT owners and Clubs over 400 samples have been collected worldwide including 33 affected dogs. A large pedigree of over 1200 DDTs has been established suggesting an autosomal recessive mode of inheritance.

To map the glaucoma loci in DTTs we performed a genome-wide association study in 23 cases and 23 controls. All controls were over 10 years old with the latest eye examination after 7 years of age. Fine-mapping of the associated region was performed with 146 additional DTT samples and 111 additional markers in the associated region

Analysis of the data revealed the disease locus on CFA8 with a genome-wide significant association (P_raw=1.6*10^-7, P_genome . The associated region spans over a 10 Mb region including a large number of genes. Fine-mapping in a larger sample set narrowed the association to 7 Mb including the best associated 2 Mb region in the middle with p-value of 3.99*10^-11.

We have mapped a canine locus on a late-onset glaucoma in DDTs and narrowed it down to a 2-Mb region. Ongoing sequencing efforts on candidate genes and the entire locus will likely result in the identification of the disease-causing mutation establishing the breed as an animal model for a hereditary glaucoma. This enables the development of a DNA test to eradicate the disease from the breed. Given that the human glaucoma locus maps to the syntenic region, identification of the mutation will lead to better understanding of the disease mechanisms in both species.

We are very excited about the early results in the project and are eagerly proceed to identify the glaucoma gene. The study is funded by Kennel Club Charitable Trust,UK, Academy of Finland, Sigrid Juselius Foundation, Biocentrum Helsinki, Jane and Aatos Erkko Foundation, University of Helsinki Research Funds and Folkhälsan.

Hannes Lohi, Professor

Department of Basic Veterinary Sciences and Medical Genetics

University of Helsinki

Folkhälsan Institute of Genetics

Tel +358-9-191-25085

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Glaucoma research: Saija Ahonen, MSc

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