AKCCHF Grant #00972 (closed)

Grant #00972: Identification of Mutations Associated with Hereditary Cataracts in Northern Breeds

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

Research Institution: Animal Health Trust

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.

Final Report Project Summary:

This study aimed to investigate the genetic cause of hereditary cataract (HC) in Northern breeds. The Investigators have collected samples from 228 dogs affected with bilateral cataract (both eyes) and 300 dogs with a clear eye examination from 15 Northern breeds, initially screening known human cataract-causing genes in 66 dogs from two of these breeds. They used a panel of 39 markers near to 20 genes involved in human inherited cataract and found no evidence for association of any markers with HC in the two breeds. Using genome-wide association (GWA) study (whole genome scanning) approaches they conducted an initial analysis of HC in the Finnish Lapphund, Icelandic Sheepdog, Samoyed and Siberian Husky. For the Samoyed they found evidence for an association with HC on chromosome 7, but no associations were identified in the other three breeds.

These initial results suggested that HC in Northern breeds is not caused by a single gene mutation and may have a more complex genetic background. This finding is not entirely surprising when it is considered that to date only a single gene, HSF4, has been implicated in the development of HC in the dog despite the fact that close to 100 breeds are known to be affected by the condition.

To detect mutations in numerous genes requires analysis of a larger number of samples using a rigorous definition for affected dogs (‘cases’) and unaffected dogs (‘controls’). Therefore for their final investigation they concentrated their efforts on four breeds that display a clinically similar form of HC and for which we have sufficient numbers of cases and controls for analysis. They have conducted a GWA scan of HC in these four breeds-the Alaskan Malamute, Siberian Husky, Karelian Bear Dog and Samoyed-using an updated high-density genome scanning array comprising around 174,000 markers spanning the DNA. Their initial analyses of these data are promising and they have found evidence of HC-associated regions for at least three of the breeds. The Investigators are currently investigating these association signals and aim to design and conduct further studies to attempt to pinpoint the causal mutations.