Katz Martin L, Khan Shahnawaz, Awano Tomoyuki, Shahid S Adam, Siakotos Aristotle N, Johnson Gary S
Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA.
Biochem Biophys Res Commun. 2005 Feb 11;327(2):541-7. doi: 10.1016/j.bbrc.2004.12.038.
A heritable neurodegenerative disease of English Setters has long been studied as a model of human neuronal ceroid-lipofuscinosis (NCL). Megablast searches of the first build of the canine genome for potential causative genes located the CLN8 gene near the q telomere of canine chromosome 37, close to a marker previously linked to English Setter NCL. Sequence analysis of the coding region from affected dogs revealed a T-to-C transition in the CLN8 gene that predicts a p.L164P missense mutation. Leucine 164 is conserved in four other mammalian species. The C allele co-segregated with the disease phenotype in a two-generation English Setter family in a pattern consistent with autosomal recessive inheritance. All four NCL-affected family members were C/C homozygotes and all four obligate carriers were C/T heterozygotes; whereas, 103 unrelated dogs were all T/T homozygotes. These findings indicate that the CLN8 T-to-C transition is the likely cause of English Setter NCL.
英国雪达犬的一种遗传性神经退行性疾病长期以来一直被作为人类神经元蜡样脂褐质沉积症（NCL）的模型进行研究。对犬类基因组首次构建版本进行的巨 blast 搜索寻找潜在致病基因，结果在犬类 37 号染色体 q 端粒附近定位到了 CLN8 基因，该位置靠近一个先前与英国雪达犬 NCL 相关的标记。对患病犬的编码区进行序列分析发现，CLN8 基因中有一个 T 到 C 的转换，预测会产生一个 p.L164P 错义突变。亮氨酸 164 在其他四个哺乳动物物种中是保守的。在一个两代英国雪达犬家族中，C 等位基因与疾病表型共分离，其模式符合常染色体隐性遗传。所有四个受 NCL 影响的家族成员都是 C/C 纯合子，所有四个必然携带者都是 C/T 杂合子；而 103 只无关的犬都是 T/T 纯合子。这些发现表明，CLN8 基因从 T 到 C 的转换可能是英国雪达犬 NCL 的病因。
