Genomic variation and gene conversion in spinal muscular atrophy: Implications for disease process and clinical phenotype
Genomic variation and gene conversion in spinal muscular atrophy: Implications for disease process and clinical phenotype
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DOI：
10.1086/513886
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发表时间：
1997-07-01
影响因子：
9.8
通讯作者：
Davies, K
中科院分区：
文献类型：
--
作者：
Campbell, L;Potter, A;Davies, K
常染色体隐性脊髓性肌萎缩症（SMA）根据发病年龄和严重程度分为三种类型：I型，重度; II型，中度; III型，轻度。在5 q13的关键区域包含一个反向重复窝藏几个基因，包括生存运动神经元（SMN）基因，神经元凋亡抑制蛋白（NAIP）基因，和p44基因，它编码的转录因子亚基。NAIP和p44的缺失在重度SMA中更常见，但没有证据表明这些基因在疾病的病理学中起作用。在>90%的SMA患者中，端粒SMN基因（SMNtel）的外显子7和8不可检测，这在一些正常的兄弟姐妹和父母中也观察到。SMNtel中的点突变和基因转换表明它在疾病中起主要作用。为了确定基因型和表型之间的相关性，我们使用脉冲场凝胶电泳绘制了缺失图。令人惊讶的是，我们的数据表明，SMA II型和III型中的突变，以前被归类为缺失，实际上是由于基因转换事件，其中SMNtel被其着丝粒对应物SMNcen取代。这导致与I型患者相比，II型和III型患者的SMNcen拷贝数更高，从而能够进行基因型/表型相关性分析。我们还展示了数百个peptidases的个别DNA含量的变化，即使在一个相对孤立的人口从芬兰。这就解释了为什么这个区域没有一致的地图。这种DNA变异可能是由于中卫星重复序列阵列，这将促进观察到的高缺失和基因转换率。
Autosomal recessive spinal muscular atrophy (SMA) is classified, on the basis of age at onset and severity, into three types: type I, severe; type II, intermediate; and type III, mild. The critical region in 5q13 contains an inverted repeat harboring several genes, including the survival motor neuron (SMN) gene, the neuronal apoptosis inhibitory protein (NAIP) gene, and the p44 gene, which encodes a transcription-factor subunit. Deletion of NAIP and p44 is observed more often in severe SMA, but there is no evidence that these genes play a role in the pathology of the disease. In >90% of all SMA patients, exons 7 and 8 of the telomeric SMN gene (SMNtel) are not detectable, and this is also observed in some normal siblings and parents. Point mutations and gene conversions in SMNtel suggest that it plays a major role in the disease. To define a correlation between genotype and phenotype, we mapped deletions, using pulsed-field gel electrophoresis. Surprisingly, our data show that mutations in SMA types II and III, previously classed as deletions, are in fact due to gene-conversion events in which SMNtel is replaced by its centromeric counterpart, SMNcen. This results in a greater number of SMNcen copies in type II and type III patients compared with type I patients and enables a genotype/phenotype correlation to be made. We also demonstrate individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explains why no consensus map of this region has been produced. This DNA variation may be due to a midisatellite repeat array, which would promote the observed high deletion and gene-conversion rate.