Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis
Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis
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DOI：
10.1073/pnas.0812297106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Coates, Joan R.
中科院分区：
文献类型：
--
作者：
Awano, Tomoyuki;Johnson, Gary S.;Coates, Joan R.
犬退行性脊髓病（DM）是一种常见于多种犬种的致死性神经退行性疾病。典型地，骨盆肢中的初始进行性上运动神经元痉挛和一般本体感受性共济失调发生在8岁或更大时。如果延迟安乐死，临床体征将上升，导致弛缓性四肢轻瘫和其他下运动神经元体征。来自38例DM受影响的彭布罗克威尔士柯基犬病例和17例相关临床正常对照的DNA样本用于全基因组关联映射，其与包含犬SOD 1基因的区域中的CFA 31标记产生最强的关联。SOD1被认为是一个区域性候选基因，因为人类SOD1的突变可导致肌萎缩侧索硬化症（ALS），这是一种成人发病的致命性麻痹性神经退行性疾病，涉及上下运动神经元。正常和患病犬的SOD1重新测序显示了G到A的转变，导致E40K错义突变。A等位基因的纯合性与5个狗品种的DM相关：彭布罗克威尔士柯基犬、拳师犬、罗得西亚脊背犬、德国牧羊犬和切萨皮克海湾寻回犬。对受影响犬的脊髓进行显微镜检查，发现髓鞘和轴突缺失，影响外侧白色物质和结合抗超氧化物歧化酶1抗体的神经元胞质内含物。这些包涵体与在具有SOD1突变的ALS患者的脊髓切片中观察到的包涵体相似。我们的研究结果确定犬DM是第一个公认的自发发生的ALS动物模型。
Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.