Scharf J M, Endrizzi M G, Wetter A, Huang S, Thompson T G, Zerres K, Dietrich W F, Wirth B, Kunkel L M
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Genet. 1998 Sep;20(1):83-6. doi: 10.1038/1753.
Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity. SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly all patients display deletions or gene conversions of the survival motor neuron (SMN1) gene. Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.
脊髓性肌萎缩症（SMA）是一种常见的隐性疾病，其特征是脊髓中的下运动神经元丧失。根据发病年龄和严重程度，该疾病已被分为三种类型。SMA I - III型均定位于5号染色体q13区域（参考文献2,3），几乎所有患者都表现出存活运动神经元（SMN1）基因的缺失或基因转换。SMN蛋白水平与疾病进程之间已建立了一些相关性；然而，SMA表型变异性的遗传基础仍不清楚，据推测，另一个修饰因子的缺失会导致I型SMA的严重程度增加。通过比较基因组学在小鼠和人类之间进化保守序列中筛选这样一个因子，我们鉴定出了一种新的转录本H4F5，它在该区域比任何先前鉴定的基因更靠近SMN1。一种在超过90%的I型SMA染色体中缺失的多拷贝微卫星标记嵌入在该基因的一个内含子中，这表明H4F5在I型SMA染色体中也高度缺失，因此是SMA的一个候选表型修饰因子。
