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首页> 外文期刊>Genes to cells : >ABLIM1 splicing is abnormal in skeletal muscle of patients with DM1 and regulated by MBNL, CELF and PTBP1
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ABLIM1 splicing is abnormal in skeletal muscle of patients with DM1 and regulated by MBNL, CELF and PTBP1

机译：DM1患者骨骼肌中ABLIM1剪接异常且受MBNL，CELF和PTBP1调节

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摘要

Myotonic dystrophy type 1 (DM1) is an RNA-mediated disorder characterized by muscle weakness, cardiac defects and multiple symptoms and is caused by expanded CTG repeats within the 3 untranslated region of the DMPK gene. In this study, we found abnormal splicing of actin-binding LIM protein 1 (ABLIM1) in skeletal muscles of patients with DM1 and a DM1 mouse model (HSA(LR)). An exon 11 inclusion isoform is expressed in skeletal muscle and heart of non-DM1 individuals, but not in skeletal muscle of patients with DM1 or other adult human tissues. Moreover, we determined that ABLIM1 splicing is regulated by several splice factors, including MBNL family proteins, CELF1, 2 and 6, and PTBP1, using a cellular splicing assay. MBNL proteins promoted the inclusion of ABLIM1 exon 11, but other proteins and expanded CUG repeats repressed exon 11 of ABLIM1. This result is consistent with the hypothesis that MBNL proteins are trapped by expanded CUG repeats and inactivated in DM1 and that CELF1 is activated in DM1. However, activation of PTBP1 has not been reported in DM1. Our results suggest that the exon 11 inclusion isoform of ABLIM1 may have a muscle-specific function, and its abnormal splicing could be related to muscle symptoms of DM1.
机译：1型强直性肌营养不良症（DM1）是一种RNA介导的疾病，以肌肉无力，心脏缺陷和多种症状为特征，是由DMPK基因的3个非翻译区域内CTG重复序列扩大引起的。在这项研究中，我们发现DM1和DM1小鼠模型（HSA（LR））的患者骨骼肌中肌动蛋白结合LIM蛋白1（ABLIM1）的异常剪接。外显子11包涵体亚型在非DM1个体的骨骼肌和心脏中表达，但在患有DM1或其他成人组织的患者的骨骼肌中不表达。此外，我们使用细胞剪接测定法确定了ABLIM1剪接受多种剪接因子的调控，包括MBNL家族蛋白，CELF1、2和6以及PTBP1。 MBNL蛋白促进ABLIM1外显子11的包含，但其他蛋白和扩展的CUG重复序列则抑制了ABLIM1外显子11。该结果与以下假设一致：MBNL蛋白被扩展的CUG重复序列捕获并在DM1中失活，而CELF1在DM1中被激活。但是，尚未在DM1中报告PTBP1的激活。我们的结果表明，ABLIM1的第11外显子包涵体亚型可能具有肌肉特异性功能，其异常剪接可能与DM1的肌肉症状有关。

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