SMN2 外显子 7 跳跃产生的降解结构域是脊髓性肌萎缩症严重程度的主要贡献者。
A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity.
机构信息
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
出版信息
Genes Dev. 2010 Mar 1;24(5):438-42. doi: 10.1101/gad.1884910.
Abstract
Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletions, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, most of the mRNA produced from SMN2 pre-mRNA is exon 7-skipped ( approximately 80%), resulting in a highly unstable and almost undetectable protein (SMNDelta7). We show that this splicing defect creates a potent degradation signal (degron; SMNDelta7-DEG) at SMNDelta7's C-terminal 15 amino acids. The S270A mutation inactivates SMNDelta7-DEG, generating a stable SMNDelta7 that rescues viability of SMN-deleted cells. These findings explain a key aspect of the SMA disease mechanism, and suggest new treatment approaches based on interference with SMNDelta7-DEG activity.
摘要
脊髓性肌萎缩症（SMA）是由运动神经元存活 1 号（SMN1）基因缺失的纯合子引起的，导致一个重复的基因 SMN2 成为 SMN 蛋白的唯一来源。然而，SMN2 前体 mRNA 产生的大部分 mRNA 都跳过了外显子 7（约 80%），导致产生一种极不稳定且几乎无法检测到的蛋白质（SMNDelta7）。我们表明，这种剪接缺陷在 SMNDelta7 的 C 端 15 个氨基酸处创建了一个有效的降解信号（degron；SMNDelta7-DEG）。SMNDelta7 中的 S270A 突变使其失活，产生稳定的 SMNDelta7，从而挽救 SMN 缺失细胞的活力。这些发现解释了 SMA 疾病机制的一个关键方面，并基于干扰 SMNDelta7-DEG 活性提出了新的治疗方法。
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