Targeted splice sequencing reveals RNA toxicity and therapeutic response in myotonic dystrophy.
Targeted splice sequencing reveals RNA toxicity and therapeutic response in myotonic dystrophy.
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DOI：
10.1093/nar/gkab022
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发表时间：
2021-02-26
影响因子：
14.9
通讯作者：
Thornton CA
中科院分区：
文献类型：
--
作者：
Tanner MK;Tang Z;Thornton CA
Biomarker-driven trials hold promise for therapeutic development in chronic diseases, such as muscular dystrophy. Myotonic dystrophy type 1 (DM1) involves RNA toxicity, where transcripts containing expanded CUG-repeats (CUGexp) accumulate in nuclear foci and sequester splicing factors in the Muscleblind-like (Mbnl) family. Oligonucleotide therapies to mitigate RNA toxicity have emerged but reliable measures of target engagement are needed. Here we examined muscle transcriptomes in mouse models of DM1 and found that CUGexp expression or Mbnl gene deletion cause similar dysregulation of alternative splicing. We selected 35 dysregulated exons for further study by targeted RNA sequencing. Across a spectrum of mouse models, the individual splice events and a composite index derived from all events showed a graded response to decrements of Mbnl or increments of CUGexp. Antisense oligonucleotides caused prompt reduction of CUGexp RNA and parallel correction of the splicing index, followed by subsequent elimination of myotonia. These results suggest that targeted splice sequencing may provide a sensitive and reliable way to assess therapeutic impact in DM1.
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DOI：
10.1085/jgp.20028741
发表时间：
2003-02
期刊：
The Journal of general physiology
影响因子：
--
作者：
Duffield M;Rychkov G;Bretag A;Roberts M
通讯作者：
Roberts M
影响因子：
16.6
作者：
Freyermuth F;Rau F;Kokunai Y;Linke T;Sellier C;Nakamori M;Kino Y;Arandel L;Jollet A;Thibault C;Philipps M;Vicaire S;Jost B;Udd B;Day JW;Duboc D;Wahbi K;Matsumura T;Fujimura H;Mochizuki H;Deryckere F;Kimura T;Nukina N;Ishiura S;Lacroix V;Campan-Fournier A;Navratil V;Chautard E;Auboeuf D;Horie M;Imoto K;Lee KY;Swanson MS;de Munain AL;Inada S;Itoh H;Nakazawa K;Ashihara T;Wang E;Zimmer T;Furling D;Takahashi MP;Charlet-Berguerand N
通讯作者：
Charlet-Berguerand N
影响因子：
1.5
作者：
BURKHOLDER, TJ;FINGADO, B;LIEBER, RL
通讯作者：
LIEBER, RL
影响因子：
16.6
作者：
Cerro-Herreros E;Sabater-Arcis M;Fernandez-Costa JM;Moreno N;Perez-Alonso M;Llamusi B;Artero R
通讯作者：
Artero R
影响因子：
11.2
作者：
FURMAN, RE;BARCHI, RL
通讯作者：
BARCHI, RL