00847-A: Mapping and Identification of the Mutation Responsible for Epilepsy in the Chinook

Project Summary

Diskinesia is a medical term to describe a movement disorder characterized by episodes in which there appears to be both involuntary movements and a decreased capacity for voluntary movements. Diskinesia is difficult to distinguish from a partial seizure. We have collected DNA and clinical information from an extended family of Chinooks, many of which exhibit repeated episodes of what appears to be diskinesia (or partial seizures). Other relatives exhibited only classic generalzed seizures and still others exhibited both types of episodes at different times. Our goal was to develop a DNA test that could be used by breeders of Chinook dogs to help them avoid matings that could produce new generations of dogs exhibiting diskinesia/seizure episodes. Before this could be accomplished, we needed to identify the chromosomal location of the causative mutation and to examine the DNA structure of the genes in this chromosomal region to identify the mutation. We attempted to determine the chromosomal location of the causative mutation with state-of-art technology known as whole-genome association analysis with so called "SNPchips" that can simultaneously analyze DNA at tens of thousands of markers at known positions scattered throughout all of the chromosomes. DNA from both cases (affected dogs) and controls (normal dogs) are analyzed and when the results from the cases and the controls are compared, markers near the causative mutation are expected to give different results than those from the controls. Our whole-genome association analysis made use of DNA from 22 cases and 19 controls analyzed with 44,147 markers. We analyzed the data with multiple statistical methods but were unable to demonstrate a convincing association at any chromosomal position. Multiple weak associations were found which are likely attributable to background variation. Then strongest of these weak associations involved markers from canine chromosome 8 where there was a gene assocated with seizures in mice; however, we were unable to find a mutation in this gene. Our failure to establish the chromosomal region responsible for Chinook diskinesia/seizure is most likely explained if there is more than one disease in the extended family or if the disease is caused by a combination of genes.

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