脊肌萎缩症(SMA)是临床婴儿致死性罕见遗传病，活婴发病率约1/10000，尚无有效疗法。其致病基因SMN1与修饰基因SMN2虽高度同源，但两者在编码区唯一差异c.840C→T却导致后者异常剪接并转录生成缺失7号外显子转录本SMN∆7。另有三篇文献提及单个碱基变异影响SMN1基因选择性剪接。除此之外，没有任何文献报道过SMN基因可变剪接和相应转录异构体与SMA疾病的分子关联。本课题组前期研究发现，SMA患者表达多种未见报道的新转录本亚型，表达谱显著区别于正常人。基于前期研究结果，本课题组拟收集正常人、携带者与患者样本30-40例，应用SMRT测序新技术，特异性分辨SMN1与SMN2基因高度相似转录本序列，鉴定新转录本亚型。从SMN基因可变剪接与转录异构体表达调控新视角出发，探究SMA疾病分子致病机制，为后续分子机理研究奠定重要基础，并为SMA基因治疗提供有用信息和潜在靶点。

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by the degeneration of spinal motor neurons and muscle atrophy and with an incidence of 1/6000-1/10000.There is no effective therapy for SMA. Although the SMN2 gene is highly homologous to the pathogenic gene SMN1, the c.840C→T change on exon 7 leads the former to produce most of the transcripts with deletion of exon7 (SMN∆7) by abnormal alternative splicing. At present, it is unclear which relationship between the pattern of alternative splicing and kind of transcripts and the SMA phenotype. Our previous results showed that abnormal SMN transcribed isoforms presented in SMA patients compared to those in controls. In addition to the SMN∆7, we also found several novel transcript subtypes those had never been reported. At present, the role of alternative splicing and transcripts in the process of SMA is still unclear. In this project, the study cohorts will be 30-40 cases included normal controls, SMA carriers and patients. SMRT (single molecular real-time) sequencing technology was used to distinguish the extremely similar transcripts from the SMN1 and SMN2 gene. The complex splicing pattern and diverse transcripts disclosed here will be helpful for further understanding the molecular mechanism of SMA. The identification of new transcript subtypes may provide potential biomarkers for SMA. This study demonstrated a new option for identification of SMN1 and SMN2 transcripts. The information obtained in this study will be useful for the researchers conducted similar studies, such as identification of complicated genes with multi-copies or pseudogenes, and may provide potential targets for SMA gene therapy.