Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.
Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.
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DOI：
10.1101/gad.300590.117
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发表时间：
2017-06-01
影响因子：
10.5
通讯作者：
Swanson MS
中科院分区：
文献类型：
--
作者：
Thomas JD;Sznajder ŁJ;Bardhi O;Aslam FN;Anastasiadis ZP;Scotti MM;Nishino I;Nakamori M;Wang ET;Swanson MS
托马斯等人。证明 RNA 错误加工是先天性强直性营养不良的主要致病因素，并提供新的小鼠模型来进一步研究组织发育过程中共转录/转录后基因调控的作用。强直性肌营养不良 1 型 (DM1) 是一种由 CUGexp RNA 表达引起的 CTG 微卫星扩增 (CTGexp) 疾病。这些突变 RNA 改变了 RNA 加工因子（包括 MBNL 蛋白）的活性，导致胎儿亚型在成人组织和 DM1 病理学中重新表达。虽然这种发病机制模型解释了成人发病的疾病，但先天性 DM (CDM) 的分子基础尚不清楚。在这里，我们检验了这样的假设：发育调控的 RNA 替代加工途径的破坏会导致 CDM 疾病。我们在婴儿 CDM 肌肉中发现了显着的选择性剪接和聚腺苷酸化异常，并且尽管大多数在成人发病的 DM1 中也被失调，但 CDM 中的失调明显更为严重。此外，对人类肌生成过程中选择性剪接的分析表明，CDM 相关外显子会经历产前 RNA 同工型转变，并预计会在子宫内被 CUGexp 相关机制破坏。为了测试这种可能性以及 MBNL 对 CDM 发病机制的贡献，我们生成了小鼠 Mbnl 双（Mbnl1；Mbnl2）和三（Mbnl1；Mbnl2；Mbnl3）肌肉特异性敲除模型，该模型概括了 CDM 的先天性肌病、基因表达和剪接病缺陷特征。这项研究表明，RNA 错误加工是 CDM 的主要致病因素，并提供了新的小鼠模型来进一步研究发育过程中共转录/转录后基因调控的作用。
Thomas et al. demonstrate that RNA misprocessing is a major pathogenic factor in congenital myotonic dystrophy and provide novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during tissue development. Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.
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影响因子：
11.1
作者：
Lee, Kuang-Yung;Li, Moyi;Manchanda, Mini;Batra, Ranjan;Charizanis, Konstantinos;Mohan, Apoorva;Warren, Sonisha A.;Chamberlain, Christopher M.;Finn, Dustin;Hong, Hannah;Ashraf, Hassan;Kasahara, Hideko;Ranum, Laura P. W.;Swanson, Maurice S.
通讯作者：
Swanson, Maurice S.
影响因子：
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作者：
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通讯作者：
Burge, Christopher B.
DOI：
10.5409/wjcp.v4.i4.66
发表时间：
2015-11-08
期刊：
World journal of clinical pediatrics
影响因子：
--
作者：
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通讯作者：
Farrar, Michelle
影响因子：
16
作者：
Batra, Ranjan;Charizanis, Konstantinos;Manchanda, Mini;Mohan, Apoorva;Li, Moyi;Finn, Dustin J.;Goodwin, Marianne;Zhang, Chaolin;Sobczak, Krzysztof;Thornton, Charles A.;Swanson, Maurice S.
通讯作者：
Swanson, Maurice S.
影响因子：
9.8
作者：
Barbé L;Lanni S;López-Castel A;Franck S;Spits C;Keymolen K;Seneca S;Tomé S;Miron I;Letourneau J;Liang M;Choufani S;Weksberg R;Wilson MD;Sedlacek Z;Gagnon C;Musova Z;Chitayat D;Shannon P;Mathieu J;Sermon K;Pearson CE
通讯作者：
Pearson CE