The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn-/- mice and results in a mouse with spinal muscular atrophy
The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn-/- mice and results in a mouse with spinal muscular atrophy
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DOI：
10.1093/hmg/9.3.333
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发表时间：
2000-02-12
影响因子：
3.5
通讯作者：
Burghes, AHM
中科院分区：
文献类型：
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作者：
Monani, UR;Sendtner, M;Burghes, AHM
近端脊髓性肌萎缩症（SMA）是人类常见的运动神经元疾病，其最严重的形式导致2岁以下儿童死亡。它是由端粒运动神经元存活基因（SMN 1）缺陷引起的，但患者保留了至少一个高度同源基因着丝粒SMN（SMN 2）的拷贝。小鼠仅具有一个运动神经元存活基因（Smn），其缺失是胚胎致死的。因此，为了获得SMA的小鼠模型，我们创建了表达人SMN 2的转基因小鼠，并将这些小鼠与空Smm（-/-）背景交配。我们发现，携带一个或两个转基因拷贝的Smn（-/-）; SMN 2小鼠在出生时具有正常数量的运动神经元，但在出生后第5天数量大大减少，随后死亡。这非常类似于人类中的严重I型SMA表型，并且是该疾病动物模型的首次报告。转基因的8个拷贝挽救了小鼠中的该表型，表明表型严重程度可通过SMN 2拷贝数调节。这些结果表明，SMA是由SMN 2基因产生SMN不足引起的，SMN 2基因表达增加可能为治疗SMA患者提供一种策略。
Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene (SMN1), but patients retain at least one copy of a highly homologous gene, centromeric SMN (SMN2), Mice possess only one survival motor neuron gene (Smn) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smm(-/-) background. We show that Smn(-/-);SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.