Submitted by Linda Heiner
Note: This Grant was approved by the AKC CHF and will be financially supported in part by the CTCA Foundation. It is expected that work on this project will begin in 2009.
Dr Simon Petersen-Jones DVetMed PhD DVOphthal DipECVO MRCVS
Associate Professor, Comparative Ophthalmology
Department of Small Animal Clinical Sciences
Michigan State University
D-208 Veterinary Medical Center
East Lansing. MI 48864
Tel: 517 353 3278
Fax: 517 355 5164
Project Duration: 2 years
Ocular melanosis causes blindness and pain to affected Cairn Terriers. Our long-term aim is to eradicate this condition from the breed. We have already collected over 400 DNA samples from both affected (126 confirmed affected Cairn Terriers) and unaffected Cairn Terriers. Additionally we have characterized the condition clinically and histologically, and identified the mode of inheritance. Building on this strong foundation and with the help of an extremely experienced collaborator, we will perform a genome-wide linkage analysis using medium density (127K SNPs) canine genotyping arrays. Positional candidate genes will then be identified and screened for the causal mutation. If it should prove necessary, our collaborator is willing to sequence the entire confidence interval to identify the causal mutation. Once we have identified the causal mutation, and confirmed it using our stored DNA samples looking for complete segregation with disease status, we will design a DNA-based test to allow breeders to screen their breeding stock for the presence of the mutation.
Ocular melanosis is an intractable, blinding and painful genetic disease that primarily affects Cairn Terriers. The affected dogs have a slowly progressive accumulation of pigmented cells within the eye that eventually impedes drainage of the intraocular fluid from the eye into the blood stream. This results in an increased pressure within the eye, known as glaucoma. Glaucoma causes both pain and vision loss. This project is to identify the gene mutation that causes ocular melanosis and to develop a test to identify affected dogs using a DNA sample. Such a test can be performed at any age and can be used to allow breeders to ensure that no more puppies are produced that will go on to develop this condition.
A. Statement of Purpose/ Hypothesis/Objectives
Our long-term objective is the eradication of ocular melanosis in the Cairn Terrier breed. In order to achieve this objective we need to identify the underlying gene mutation and then develop a DNA-based diagnostic test to genotype Cairn Terriers for the mutation. Such a test will be provided to breeders to screen their breeding stock for the mutation allowing the disease to be eradicated. In the early stages of the eradication phase the test will also be useful to identify affected dogs before they develop clinical signs of the condition. This will enable closer monitoring of dogs that have the mutation so that they can be treated as soon as clinical problems develop. Although there is currently no treatment for the condition that is effective in the long-term, successful management of glaucoma in the early stages can prolong the duration of useful vision and keep the eyes comfortable for longer.
Our hypothesis, based on our previous phenotyping and pedigree analysis work, is that ocular melanosis is inherited in an autosomal dominant fashion and has a single necessary locus involving a gene that is either involved in melanin formation pathways (specific within the uvea) or control of the biologic behavior of anterior uveal melanocytes.
To test our hypothesis and move towards achieving our long-term objectives we have 3 specific objectives:
Specific Objective 1: To use the recently available canine medium density single-nucleotide-polymorphism (SNP) microarrays to map the ocular melanosis locus.
Specific Objective 2: To identify the causal gene mutation for ocular melanosis by sequencing of the coding region and intron/exon boundaries of positional candidate genes identified by the mapping performed as specific objective 1.
Specific Objective 3: Development of a DNA-based test for the causal mutation for ocular melanosis.