Clinical and basic scientific investigation of spinal muscular atrophy towards the elucidation of disease mechanism and the development of therapy

脊髓性肌萎缩症(SMA)是一种常染色体隐性遗传病，分为三种类型。SMN(存活型运动神经元)基因是SMA的决定基因，命名为SMNt和SMNC。虽然SMA的病因被认为是SMNt缺失，但三种类型的临床症状严重程度不同，表现为SMNt缺失。为了阐明临床变异的基础，我们对29例日本SMA患者的SMN基因的DNA和mRNA进行了分析。一种大的基因缺失，包括SMN和其他在重症临床类型中被识别的基因。我们检测到一个杂交基因，即从SMNt到SMNC的基因转化产物。我们还对克隆的SMN外显子6、7和8进行了序列分析，获得了1例SMN外显子7的端粒序列。提示该患者可能发生了以SMNt取代SMNC的序列转换。综上所述，SMNt和修饰基因的缺失使表型更加严重，而部分基因转换事件是导致表型较温和的原因。

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, classified into three types. The SMN (survival motor neuron) gene has been identified as a SMA-determining gene, designated SMNt and SMNc. Although the etiology of SMA is regarded as deletion of SMNt, the severity of clinical symptom is different among three types, and they show the same deletion of SMNt. In order to elucidate the basis of clinical variation, we analyzed the DNA and mRNA of the SMN gene in the Japanese 29 SMA patients. A large gene deletion including SMN and other genes as recognized in severe clinical type. We detected a hybrid gene, the products of gene conversion from SMNt to SMNc. Hybrid genes were found by a total nine patients, only in type II and III. We also performed sequence analysis of the cloned RT-PCR products of SMN exons 6,7 and 8. We obtained telomeric sequence of exon 7 of one patient. It suggests that sequence conversion replacing SMNc with SMNt may have occurred at mRNA level in this patient. In conclusion, deletion of the SMNt and the modifier genes made the phenotype more severe, and partial gene conversion event was the explanation for the milder phenotype.