Inserm U614, IFRMP, Institute for Biomedical Research, Rouen University Medical School, Rouen, France.
Hum Mutat. 2011 Sep;32(9):989-94. doi: 10.1002/humu.21528.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting, in most cases, from homozygous deletions of the SMN1 gene or, in rare cases, from SMN1 intragenic mutations. Here we describe the identification and characterization of c.835-3C>T, a novel SMA-causing mutation detected in the intron 6 of the single SMN1 allele of a type IV SMA patient. We demonstrate both ex vivo and in vivo that c.835-3C>T is a deleterious splicing mutation that induces a modest but unequivocal exclusion of exon 7 from the SMN1 transcripts, its "leakiness" explaining the exceptionally mild phenotype of this patient. This mutation creates a putative high-affinity binding site for the splicing repressor protein hnRNP A1 overlapping the splice acceptor site of exon 7 (UAG|GGU). Our findings support the current therapeutic strategies aiming at correcting exon 7 splicing in SMA patients, and bring clues about the level of exon 7 inclusion required to achieve a therapeutic effect.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，大多数情况下是由于 SMN1 基因的纯合缺失或极少数情况下由于 SMN1 基因内突变引起的。在此，我们描述了在四型 SMA 患者的单个 SMN1 等位基因的内含子 6 中检测到的 c.835-3C>T，这是一种新的 SMA 致病突变的鉴定和特征。我们证明 c.835-3C>T 是一种有害的剪接突变，它导致外显子 7 从 SMN1 转录本中适度但明确的排除，其“渗漏性”解释了该患者异常轻微的表型。该突变创建了一个与剪接受体位点（UAG|GGU）重叠的、具有高亲和力结合 RNA 结合蛋白 hnRNP A1 的内含子 7 的假定结合位点。我们的发现支持目前旨在纠正 SMA 患者外显子 7 剪接的治疗策略，并提供了关于实现治疗效果所需的外显子 7 包含水平的线索。
