A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2
A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2
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DOI：
10.1093/hmg/8.7.1177
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发表时间：
1999-07-01
影响因子：
3.5
通讯作者：
McPherson, JD
中科院分区：
文献类型：
--
作者：
Monani, UR;Lorson, CL;McPherson, JD
脊髓性肌萎缩症（SMA）是一种隐性疾病，其特征是脊髓运动神经元的丢失。它是由端粒运动神经元生存1（SMN 1）基因突变引起的。着丝粒运动神经元存活基因2（SMN 2）在几乎相同的拷贝基因内的改变不产生已知的表型效应。这两个基因的外显子只有两个核苷酸不同，两者都不会改变编码的氨基酸。在基因组水平上，只有五个核苷酸，区分这两个基因彼此已被报道。这两个基因的整个基因组序列尚未确定。因此，可能解释为什么SMN 1是SMA基因的差异并不明显。在这项研究中，我们已经完全测序和比较基因组克隆含有SMN基因。这两个基因显示出惊人的相似性，两个不同但功能性基因之间的同源性是前所未有的。两个SMN基因之间相似的32 kb区域中的唯一关键差异是外显子7内6 bp的C->T碱基变化。SMN基因中的这种改变而不是其他变异影响基因的剪接模式。来自SMN 1基因座的大部分转录物是全长的，而SMN 2基因座产生的大部分转录物缺乏外显子7。我们认为外显子7核苷酸的变化影响外显子剪接增强子的活性。在SMA患者中，SMN 1缺失但存在SMN 2导致全长SMN转录物水平降低，因此导致SMN蛋白水平降低，从而导致SMA。
Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinal cord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within an almost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known phenotypic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encoded amino acids. At the genomic level, only five nucleotides that differentiate the two genes from one another have been reported. The entire genomic sequence of the two genes has not been determined. Thus, differences which might explain why SMN1 is the SMA gene are not readily apparent. In this study, we have completely sequenced and compared genomic clones containing the SMN genes. The two genes show striking similarity, with the homology being unprecedented between two different yet functional genes. The only critical difference in an similar to 32 kb region between the two SMN genes is the C-->T base change 6 bp inside exon 7. This alteration but not other variations in the SMN genes affects the splicing pattern of the genes, The majority of the transcript from the SMN1 locus is full length, whereas the majority of the transcript produced by the SMN2 locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon splice enhancer. In SMA patients, the loss of SMN1 but the presence of SMN2 results in low levels of full-length SMN transcript and therefore low SMN protein levels which causes SMA.