Coovert D D, Le T T, McAndrew P E, Strasswimmer J, Crawford T O, Mendell J R, Coulson S E, Androphy E J, Prior T W, Burghes A H
Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus 43210, USA.
Hum Mol Genet. 1997 Aug;6(8):1205-14. doi: 10.1093/hmg/6.8.1205.
The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.
38 kDa的生存运动神经元（SMN）蛋白由两个普遍表达的基因编码：端粒SMN（SMN(T)）和着丝粒SMN（SMN(C)）。SMN(T)而非SMN(C)的突变会导致近端脊髓性肌萎缩症（SMA），这是一种常染色体隐性疾病，会导致运动神经元丧失。SMN存在于细胞质和细胞核中。核形式位于称为宝石样小体（gems）的结构中。使用一组抗SMN抗体，我们证明SMN蛋白由SMN(T)和SMN(C)基因共同表达。对患有不同临床严重程度SMA的患者的成纤维细胞进行蛋白质免疫印迹分析显示，SMN蛋白的量有适度减少，尤其是在I型（最严重）患者中。对SMA患者成纤维细胞的免疫细胞化学分析表明，I型SMA患者的宝石样小体数量显著减少，且宝石样小体数量与临床严重程度相关。利用原代成纤维细胞与表型的这种相关性可能成为一种在易于获取的组织中有用的诊断工具。SMN在脑、肾和肝中高水平表达，在骨骼肌和心肌中中等水平表达，在成纤维细胞和淋巴细胞中低水平表达。在SMA患者中，肌肉和淋巴母细胞中的SMN水平适度降低。相比之下，正常人和非SMA疾病对照者脊髓中的SMN高水平表达，但I型患者脊髓中的SMN表达减少了100倍。I型SMA脊髓中SMN的显著减少与这种运动神经元疾病的特征一致。我们认为，I型患者中SMN(T)的破坏导致运动神经元中SMN的丧失，从而导致这些神经元的退化。
