Splicing biomarkers of disease severity in myotonic dystrophy.
Splicing biomarkers of disease severity in myotonic dystrophy.
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DOI：
10.1002/ana.23992
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发表时间：
2013-12
影响因子：
11.2
通讯作者：
Thornton, Charles A.
中科院分区：
文献类型：
--
作者：
Nakamori, Masayuki;Sobczak, Krzysztof;Puwanant, Araya;Welle, Steve;Eichinger, Katy;Pandya, Shree;Dekdebrun, Jeannne;Heatwole, Chad R.;McDermott, Michael P.;Chen, Tian;Cline, Melissa;Tawil, Rabi;Osborne, Robert J.;Wheeler, Thurman M.;Swanson, Maurice S.;Moxley, Richard T., III;Thornton, Charles A.
开发强直性肌营养不良1型（DM 1）和2型（DM 2）疾病严重程度和治疗反应的RNA剪接生物标志物。在一个发现队列中，我们使用微阵列对DM1和DM2中的选择性剪接进行了全局分析。新鉴定的剪接变化与先前的数据相结合，以创建一组50个推定的剪接缺陷。在50名DM 1受试者的验证队列中，我们测量了踝关节背屈（ADF）的强度，然后获得胫骨前肌（TA）的针吸活检以分析肌肉RNA中的剪接事件。在疾病对照中评估DM相关剪接缺陷的特异性。Southern杂交检测CTG在肌肉组织中的扩增量。通过使用反义寡核苷酸（ASO）降低毒性RNA的水平，在转基因小鼠中评估剪接缺陷的可逆性。在验证队列中，在TA肌肉中确认了42个剪接缺陷。其中，20个事件显示出与ADF减弱相关的分级变化。其他五个剪接事件受到强烈影响，在DM 1与正常ADF强度的主题。与疾病对照和小鼠模型的比较表明，剪接变化是DM特异性的，主要归因于MBNL1螯合，并且在小鼠中通过靶向敲低毒性RNA而可逆。在肌肉组织中，CTG扩增的大小与剪接缺陷和弱化无关。骨骼肌可变剪接的改变可以作为强直性肌营养不良症疾病严重程度和治疗反应的生物标志物。
To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). In a discovery cohort we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.
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影响因子：
56.9
作者：
Lee, EY;Marcucci, M;De Camilli, P
通讯作者：
De Camilli, P
影响因子：
11.4
作者：
Miller, JW;Urbinati, CR;Swanson, MS
通讯作者：
Swanson, MS
影响因子：
2.2
作者：
Hilbert JE;Kissel JT;Luebbe EA;Martens WB;McDermott MP;Sanders DB;Tawil R;Thornton CA;Moxley RT 3rd;Registry Scientific Advisory Committee
通讯作者：
Registry Scientific Advisory Committee
DOI：
10.1007/978-0-387-77374-2_13
发表时间：
2007-01-01
期刊：
ALTERNATIVE SPLICING IN THE POSTGENOMIC ERA
影响因子：
--
作者：
Orengo, James P.;Cooper, Thomas A.
通讯作者：
Cooper, Thomas A.
影响因子：
56.9
作者：
Liquori, CL;Ricker, K;Ranum, LPW
通讯作者：
Ranum, LPW