Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos
Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos
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DOI：
10.1073/pnas.94.18.9920
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发表时间：
1997-09-02
影响因子：
11.1
通讯作者：
Sendtner, M
中科院分区：
文献类型：
--
作者：
Schrank, B;Gotz, R;Sendtner, M
近端脊髓性肌萎缩症是一种常染色体隐性遗传的人类脊髓运动神经元疾病，主要在婴儿和儿童期发病，导致肌无力。估计杂合子频率为1/40，是最常见的婴儿致死性单基因疾病;轻度形式代表第二常见的儿科神经肌肉疾病。通过定位克隆，在染色体5 q13上发现了两个候选基因--运动神经元存活基因（survivalmotorneuron，SMN）和神经元凋亡抑制蛋白（neuronalapoptosis inhibitoryprotein）。然而，这些基因的功能影响和导致运动神经元退化的机制仍有待确定。为了分析SMN基因产物在体内的作用，我们产生了SMN缺陷小鼠。与包含两个拷贝的人类基因组相比，小鼠基因组仅包含一个SMN基因。具有纯合SMN破坏的小鼠在早期胚胎发育期间显示大量细胞死亡，表明SMN基因产物对于细胞存活和功能是必需的。
Proximal spinal muscular atrophy is an autosomal recessive human disease of spinal motor neurons leading to muscular weakness with onset predominantly in infancy and childhood. With an estimated heterozygote frequency of 1/40 it is the most common monogenic disorder lethal to infants; milder forms represent the second most common pediatric neuromuscular disorder. Two candidate genes-survival motor neuron (SMN) and neuronal apoptosis inhibitory protein have been identified on chromosome 5q13 by positional cloning. However, the functional impact of these genes and the mechanism leading to a degeneration of motor neurons remain to be defined. To analyze the role of the SMN gene product in vivo we generated SMN-deficient mice. In contrast to the human genome, which contains two copies, the mouse genome contains only one SMN gene. Mice with homozygous SMN disruption display massive cell death during early embryonic development, indicating that the SMN gene product is necessary for cellular survival and function.