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Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy
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نویسنده
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wagner s.d. ,struck a.j. ,gupta r. ,farnsworth d.r. ,mahady a.e. ,eichinger k. ,thornton c.a. ,wang e.t. ,berglund j.a.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 9
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چکیده
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Alternative splicing is a regulated process that results in expression of specific mrna and protein isoforms. alternative splicing factors determine the relative abundance of each isoform. here we focus on mbnl1,a splicing factor misregulated in the disease myotonic dystrophy. by altering the concentration of mbnl1 in cells across a broad dynamic range,we show that different splicing events require different amounts of mbnl1 for half-maximal response,and respond more or less steeply to mbnl1. motifs around mbnl1 exon 5 were studied to assess how cis-elements mediate the mbnl1 dose-dependent splicing response. a framework was developed to estimate mbnl concentration using splicing responses alone,validated in the cell-based model,and applied to myotonic dystrophy patient muscle. using this framework,we evaluated the ability of individual and combinations of splicing events to predict functional mbnl concentration in human biopsies,as well as their performance as biomarkers to assay mild,moderate,and severe cases of dm. © 2016 wagner et al.
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آدرس
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department of chemistry and biochemistry,institute of molecular biology,university of oregon,eugene,or, United States, department of chemistry and biochemistry,institute of molecular biology,university of oregon,eugene,or, United States, department of biology,johns hopkins university,baltimore,md, United States, department of biology,institute of molecular biology,university of oregon,eugene,or, United States, department of chemistry and biochemistry,institute of molecular biology,university of oregon,eugene,or, United States, department of neurology,university of rochester medical center,rochester,ny, United States, department of neurology,university of rochester medical center,rochester,ny, United States, department of biology,massachusetts institute of technology,cambridge,ma,united states,koch institute for integrative cancer research,massachusetts institute of technology,cambridge,ma,united states,department of biochemistry & molecular biology,center for neurogenetics,university of florida,gainesville,fl, United States, department of chemistry and biochemistry,institute of molecular biology,university of oregon,eugene,or,united states,department of biochemistry & molecular biology,center for neurogenetics,university of florida,gainesville,fl, United States
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Authors
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