Research Programs Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland.
PLoS One. 2012;7(3):e33549. doi: 10.1371/journal.pone.0033549. Epub 2012 Mar 23.
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.
癫痫是犬类最常见的神经障碍，在某些特定品种中发病率为 0.5%至 20%不等。犬癫痫可以从病因上定义为特发性或症状性。癫痫发作可分为局灶性伴或不伴继发全面性发作，或原发性全面性发作。在不同品种中，已经确定了 9 个基因与症状性（储存疾病）和 1 个基因与特发性癫痫有关。然而，常见犬癫痫的遗传背景仍不清楚。我们研究了比利时牧羊犬的癫痫临床和遗传背景。我们收集了 159 例病例和 148 例对照，并通过癫痫问卷和临床检查确认了癫痫的存在。磁共振成像正常，而发作间期脑电图显示在受影响的临床检查犬中存在异常和可变焦点。在 40 例病例和 44 例对照中使用 Affymetrix 50K SNP 芯片进行的全基因组关联研究将癫痫基因座映射到 CFA37 上，在独立队列（81 例病例和 88 例对照；合并 p=9.70×10⁻¹⁰，OR=3.3）中得到了复制。精细映射研究定义了一个包含 12 个基因的约 1 Mb 区域，其中没有一个是已知的癫痫基因或编码离子通道的基因。对两个候选基因 KLF7 和 ADAM23 进行了外显子测序。在 KLF7 中没有发现变异，但在 ADAM23 基因中存在一个高度相关的非同义变异 G1203A（R387H）（p=3.7×10⁻⁸，OR=3.9 为纯合子）。ADAM23 基因内的两个 SNP 单倍型的纯合性赋予癫痫的最高风险（p=6.28×10⁻¹¹，OR=7.4）。ADAM23 与已知的癫痫蛋白 LGI1 和 LGI2 相互作用。然而，我们的数据表明 ADAM23 变体是一种多态性，我们已经开始在整个基因座上进行靶向重测序研究，以确定致病突变。这将使受影响的品种成为一种新的治疗模型，有助于开发用于繁殖的 DNA 测试，并为人类特发性癫痫引入一个新的候选基因。
