Abstract
Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10−10, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10−8, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10−11, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.
Highlights
Epilepsy is one of the most common neurological diseases affecting 1–3% of the human population [1]
As part of our larger ongoing program to tackle the genetics of canine epilepsies, we have developed further resources to map the IE genes in Belgian Shepherds (BS) suffering from epilepsy dominated by focal seizures with or without secondary generalization [18]
We identified the highest risk of epilepsy among individuals homozygous for the haplotype composed of the risk-conferring alleles of the G1203A and BICF2P890779 variants (p = 6.28610211 OR = 7.4, 95% CI: 3.9–14.0) which are in strong linkage disequilibrium (LD) with each other (D9 = 0.87)
Summary
Epilepsy is one of the most common neurological diseases affecting 1–3% of the human population [1]. Epilepsy refers to a group of chronic neurological symptoms characterized by recurrent unprovoked seizures. Seizures are transient symptoms of abnormal, excessive or synchronous neuronal activity in the brain and can be classified into two major types: focal-onset and primarily generalized. In focal-onset seizures, the synchronized activity is restricted to a single part of the cortex, and may or may not subsequently spread to recruit the thalamocortical pathways and result in secondary generalization. Focal motor seizures may be characterized by elementary motor events, which consist of a single type of stereotyped contraction of a muscle or group of muscles or by autonomic features or paroxysms of behavioral signs probably corresponding to disturbance of higher cerebral activity in humans known as psychic seizures [2]. Only a few risk genes are known to date, and a large number of genes contributing to human epilepsy still remain to be identified [8]
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