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

脊髓性肌萎缩症的临床和基础科学研究，以阐明疾病机制和开发治疗方法

基本信息

批准号：
12470173
负责人：
SAITO Kayoko
金额：
$ 8.58万
依托单位：
Tokyo Women's Medical University of School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

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.

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（存活运动神经元）基因已被确定为sma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，表现出相同的SMNt缺失。为了阐明临床变异的基础，我们分析了日本29例SMA患者的SMN基因的DNA和mRNA。包括SMN和其他基因在内的大量基因缺失，在严重的临床型中得到认可。我们检测到一个杂交基因，从SMNt到SMNc基因转化的产物。共有9例患者发现杂交基因，仅在II型和III型中发现。我们还对克隆的SMN外显子6,7和8的RT-PCR产物进行了序列分析。我们获得了一例患者第7外显子的端粒序列。这表明在该患者中，用SMNt取代SMNc的序列转换可能发生在mRNA水平上。综上所述，SMNt和修饰基因的缺失使表型更为严重，部分基因转换事件可以解释表型较轻的原因。