AKCCHF Grant 972 report

Grant972: Identification of Mutations Associated with Hereditary Cataracts in Northern Breeds

Principal Investigator: Dr. Cathryn Mellersh, Ph.D.

Research Institution: Animal Health Trust

Grant Amount: $100,000.00

Start Date: 7/1/2008 End Date: 6/30/2010

Progress Report: 18 month

Report Received: 2/5/2010

Original Project Description:

Background: Hereditary cataracts (HC) are a leading cause of blindness in dogs and thus represent a significant health and welfare burden to many breeds of dog. The work outlined in this proposal aims to identify the genetic cause of HC in Northern breeds, a closely related group of breeds that collectively suffer a high incidence of HC.

Objective: A successful outcome of the project will enable the researchers to develop diagnostic DNA tests that breeders can use to determine whether their dogs are affected with HC and whether they will pass the condition onto their offspring. DNA tests enable carrier and even affected dogs to be safely bred from, if they are good examples of their breed and they are only mated to dogs that have tested clear of HC, thus keeping their valuable genes in the population without risking the production of affected offspring.

Original Grant Objectives:

Objective 1: Increase the numbers of samples to at least 20 cases and 20 controls for 13 Northern breeds.

Objective 2: Genotype the cases and controls of each breed with microsatellites closely linked to approximately 25 genes candidate genes known to be associated with inherited forms of cataract in humans, to identify any that are linked to HC in the dog.

Objective 3: Genotype 40 samples (20 cases and 20 controls) for two breeds, the Siberian Husky and the Samoyed, with high-density SNP (single nucleotide polymorphism) arrays and carry out linkage or association analysis to identify genomic regions associated with HC in each breed.

Objective 4: Genotype SNPs from associated region(s) in cases and controls of other Northern breeds, to determine whether cases from all breeds share a common haplotype, which would indicate a single mutation is likely responsible for HC in all Northern breeds (linkage disequilibrium mapping).

Objective 5: Sequence candidate genes within the HC critical region to identify causal mutation(s).

Objective 6: Investigate other, non-Northern breeds with HC to identify any that share causal mutations identified during this project.

Objective 7: Develop diagnostic DNA test which will be offered to breeders.

Report to Grant Sponsor from Investigator:

The collaborative research project between Drs Cathryn Mellersh (Animal Health Trust, UK) and Hannes Lohi (University of Helsinki, Finland) aimed at identifying mutations associated with Hereditary Cataract (HC) in Northern breeds is going well. We have collected good numbers of samples from affected and control dogs but we would like to encourage owners of any Northern breed affected with cataracts to consider donating samples from their dogs to this project.

So far, the research has undertaken WGSs with samples from 128 dogs of 4 different breeds. In previous studies undertaken by both the Mellersh and Lohi labs this number of samples has been sufficient to successfully identify regions of the genome significantly associated with monogenic conditions. Unfortunately for HC in Northern breeds we have obtained only modest evidence for association with HC thus far, indicating that the condition is probably complex in these breeds, involving variants in more than one gene. This conclusion is consistent with our findings in other breeds; for example other WGASs currently being undertaken in the Mellersh lab involving the analysis of 40 cases and 75 controls of the same breed have identified genomic regions that are only modestly associated with HC. Alternatively, there are clinically similar but genetically distinct forms of cataract segregating in these breeds. For both of these scenarios the solution will be to continue collecting samples from robustly diagnosed cases and controls and to undertake WGSs with additional samples.

In the latter stages of this project, therefore, we plan to undertake WGSs with all the remaining cases we have at our disposal, for the breeds we have already genotyped to date. We will also genotype a similar number of additional controls.