Department of Biomedicine and Prevention, University 'Tor Vergata', Roma 00133, Italy.
Cell Death Dis. 2013 Aug 15;4(8):e770. doi: 10.1038/cddis.2013.291.
Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.
肌强直性营养不良 1 型（DM1）是成年人中最常见的肌肉营养不良形式。这种疾病是一种 RNA 显性疾病，由 DMPK 基因中 CTG 重复扩展引起，导致前体 mRNA 的选择性剪接失调。含有外显子 5 的更长的肌肉盲样蛋白 1（MBNL1）转录本和相应的蛋白质同工型（MBNL142-43）在 DM1 肌肉中被发现过度表达，并专门定位于细胞核中。体外实验表明，MBNL142-43 通过其富含脯氨酸的基序与Src 家族激酶（SFKs）的Src 同源结构域 3 结合，增强了 SFK 的活性。值得注意的是，这种关联在 DM1 肌肉和肌管中也得到了证实。通过针对 Ex5-MBNL142-43 的 siRNA 介导的恢复，成功地减少了 Lyn 和 MBNL142-43 蛋白的核定位，并降低了酪氨酸磷酸化蛋白的水平。我们的研究结果表明，基于改变的磷酸酪氨酸信号通路，DM1 发病机制中存在另一种分子机制。
