دورية أكاديمية
أعرض في EDS

A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I.

التفاصيل البيبلوغرافية
العنوان: A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I.
المؤلفون: Zhang F; Rare Disease Research Unit., Bodycombe NE; Medicine Design, Worldwide Research and Development, Pfizer, Cambridge, MA 02139, USA., Haskell KM; Pharmacokinetics, Dynamics and Metabolism - New Chemical Entities, Worldwide Research and Development, Pfizer, CT 06340, USA., Sun YL; Rare Disease Research Unit., Wang ET; Center for Neurogenetics, University of Florida, Gainesville, FL 32610, USA., Morris CA; Rare Disease Research Unit., Jones LH; Medicine Design, Worldwide Research and Development, Pfizer, Cambridge, MA 02139, USA., Wood LD; Rare Disease Research Unit., Pletcher MT; Rare Disease Research Unit.
المصدر: Human molecular genetics [Hum Mol Genet] 2017 Aug 15; Vol. 26 (16), pp. 3056-3068.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
مواضيع طبية MeSH: Myotonic Dystrophy/*drug therapy , Myotonic Dystrophy/*metabolism , Myotonin-Protein Kinase/*genetics , RNA-Binding Proteins/*biosynthesis , RNA-Binding Proteins/*genetics , Small Molecule Libraries/*pharmacology, 3' Untranslated Regions ; Alternative Splicing ; Exons ; Flow Cytometry/methods ; HeLa Cells ; Humans ; Myotonic Dystrophy/genetics ; Myotonin-Protein Kinase/metabolism ; RNA Precursors/metabolism ; RNA Splicing/drug effects ; RNA-Binding Proteins/metabolism ; Trinucleotide Repeat Expansion ; Trinucleotide Repeats
مستخلص: Myotonic dystrophy Type 1 (DM1) is a rare genetic disease caused by the expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified. Here, we engineered a ZsGreen tag into the endogenous MBNL1 locus in HeLa cells and established a flow cytometry-based screening system to identify compounds that increase MBNL1 level. The initial screen of small molecule compound libraries identified more than thirty hits that increased MBNL1 expression greater than double the baseline levels. Further characterization of two hits revealed that the small molecule HDAC inhibitors, ISOX and vorinostat, increased MBNL1 expression in DM1 patient-derived fibroblasts and partially rescued the splicing defect caused by (CUG)exp repeats in these cells. These findings demonstrate the feasibility of this flow-based cytometry screen to identify both small molecule compounds and druggable targets for MBNL1 upregulation.
(© The Author 2017. Published by Oxford University Press.)
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معلومات مُعتمدة: DP5 OD017865 United States OD NIH HHS
المشرفين على المادة: 0 (3' Untranslated Regions)
0 (DMPK protein, human)
0 (MBNL1 protein, human)
0 (RNA Precursors)
0 (RNA-Binding Proteins)
0 (Small Molecule Libraries)
EC 2.7.11.1 (Myotonin-Protein Kinase)
تواريخ الأحداث: Date Created: 20170524 Date Completed: 20180117 Latest Revision: 20181113
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5886090
DOI: 10.1093/hmg/ddx190
PMID: 28535287
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2083
DOI:10.1093/hmg/ddx190