Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene
Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene
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DOI：
10.1371/journal.pgen.1000499
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发表时间：
2009-05-01
期刊：
影响因子：
4.5
通讯作者：
Andersson, Leif
中科院分区：
文献类型：
--
作者：
Baranowska, Izabella;Jaderlund, Karin Hultin;Andersson, Leif
感觉共济失调神经病（SAN）是最近发现的一种神经系统疾病在金毛猎犬。家谱分析显示，所有受影响的狗都属于一个母系，统计分析显示，这种疾病有线粒体起源。在对7只患病犬的线粒体全基因组重新测序后，在5304号位置发现了线粒体tRNA（Tyr）基因的一个碱基对缺失。在18个不同品种的狗或6只狼中没有发现这种缺失，排除了这种常见多态性的可能性。这种突变可以追溯到生活在20世纪70年代的所有受影响狗的共同祖先。我们使用定量寡核苷酸结扎法来确定感染犬和对照犬的血液和组织样本的异质性程度。受影响的狗及其一至四度亲缘有0-11%的野生型（wt）序列，而更远的亲缘在5% - 60%的wt序列之间，所有不相关的金毛猎犬有100%的wt序列。Northern blot分析显示，与对照组相比，受影响犬的tRNA（Tyr）稳态水平低10倍。5只受影响的狗中有4只表现出线粒体ATP产生率和呼吸链酶活性的下降，同时肌肉组织的形态改变，与人类线粒体病理报告的变化相似。总之，这些结果提供了确凿的证据，证明线粒体tRNA（Tyr）基因的缺失是SAN的致病突变。
Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNA(Tyr) gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0-11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNA(Tyr) had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNA(Tyr) gene is the causative mutation for SAN.