DiDonato C J, Ingraham S E, Mendell J R, Prior T W, Lenard S, Moxley R T, Florence J, Burghes A H
Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, USA.
Ann Neurol. 1997 Feb;41(2):230-7. doi: 10.1002/ana.410410214.
The spinal muscular atrophy-determining gene, survival motor neuron (SMN), is present in two copies, telSMN and cenSMN, which can be distinguished by base-pair changes in exons 7 and 8. The telSMN gene is often absent in spinal muscular atrophy patients, which could be due to deletion or sequence conversion (telSMN conversion to cenSMN giving rise to two cenSMN genes). To test for conversion events in spinal muscular atrophy, we amplified a 1-kb fragment that spanned exons 7 and 8 of SMN from 5 patients who retained telSMN exon 8 but lacked exon 7. In all patients, sequence analysis demonstrated that cenSMN exon 7 was adjacent to telSMN exon 8, indicating conversion. All 5 patients with this mutation had type II or III spinal muscular atrophy, strongly supporting an association with chronic spinal muscular atrophy. We also identified 3 families in which 2 siblings had no detectable telSMN but presented with markedly different phenotypes. We suggest that sequence conversion is a common event in spinal muscular atrophy and is associated with the milder form of the disease. The severity, however, can be modified in either a positive or negative direction by other factors that influence splicing or expression of the sequence converted SMN gene.
脊髓性肌萎缩症决定基因，即生存运动神经元（SMN）基因，有两个拷贝，即端粒SMN（telSMN）和着丝粒SMN（cenSMN），可通过外显子7和8中的碱基对变化来区分。脊髓性肌萎缩症患者中通常不存在telSMN基因，这可能是由于缺失或序列转换（telSMN转换为cenSMN，从而产生两个cenSMN基因）。为了检测脊髓性肌萎缩症中的转换事件，我们从5名保留telSMN外显子8但缺少外显子7的患者中扩增了一个跨越SMN外显子7和8的1 kb片段。在所有患者中，序列分析表明cenSMN外显子7与telSMN外显子8相邻，表明发生了转换。所有5名携带此突变的患者均患有II型或III型脊髓性肌萎缩症，这有力地支持了其与慢性脊髓性肌萎缩症的关联。我们还鉴定出3个家系，其中2名兄弟姐妹检测不到telSMN，但表现出明显不同的表型。我们认为序列转换是脊髓性肌萎缩症中的常见事件，并且与疾病的较轻形式相关。然而，疾病的严重程度可受到其他影响剪接或序列转换后的SMN基因表达的因素的正向或负向调节。
