دورية أكاديمية
أعرض في EDS

Reversible cardiac disease features in an inducible CUG repeat RNA-expressing mouse model of myotonic dystrophy.

التفاصيل البيبلوغرافية
العنوان: Reversible cardiac disease features in an inducible CUG repeat RNA-expressing mouse model of myotonic dystrophy.
المؤلفون: Rao AN; Department of Molecular and Cellular Biology., Campbell HM; Department of Molecular Physiology and Biophysics, and.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA., Guan X; Computational Biology Program, Oregon Health & Science University, Portland, Oregon, USA., Word TA; Department of Molecular Physiology and Biophysics, and., Wehrens XH; Department of Molecular Physiology and Biophysics, and.; Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA., Xia Z; Computational Biology Program, Oregon Health & Science University, Portland, Oregon, USA.; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA., Cooper TA; Department of Molecular and Cellular Biology.; Department of Molecular Physiology and Biophysics, and.; Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
المصدر: JCI insight [JCI Insight] 2021 Mar 08; Vol. 6 (5). Date of Electronic Publication: 2021 Mar 08.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
مواضيع طبية MeSH: Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/pathology, Myotonic Dystrophy/*genetics , Myotonin-Protein Kinase/*genetics, Alternative Splicing ; Animals ; Cells, Cultured ; Humans ; Mice ; Mice, Transgenic ; Protein Isoforms/metabolism ; Trinucleotide Repeat Expansion
مستخلص: Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.
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معلومات مُعتمدة: F30 HL140782 United States HL NHLBI NIH HHS; T32 HL139430 United States HL NHLBI NIH HHS; R01 AR045653 United States AR NIAMS NIH HHS; R01 HL091947 United States HL NHLBI NIH HHS; R01 HL147108 United States HL NHLBI NIH HHS; R01 DK114356 United States DK NIDDK NIH HHS; R01 HL045565 United States HL NHLBI NIH HHS; R01 AR060733 United States AR NIAMS NIH HHS; P30 CA125123 United States CA NCI NIH HHS; K01 LM012877 United States LM NLM NIH HHS; UM1 HG006348 United States HG NHGRI NIH HHS; R01 HL089598 United States HL NHLBI NIH HHS; P30 DK056338 United States DK NIDDK NIH HHS; R01 HL147020 United States HL NHLBI NIH HHS; R01 HL117641 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: Arrhythmias; Cardiology; Cell Biology; RNA processing
المشرفين على المادة: 0 (DMPK protein, human)
0 (Protein Isoforms)
EC 2.7.11.1 (Myotonin-Protein Kinase)
تواريخ الأحداث: Date Created: 20210126 Date Completed: 20220110 Latest Revision: 20220110
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC8021116
DOI: 10.1172/jci.insight.143465
PMID: 33497365
قاعدة البيانات: MEDLINE
الوصف
تدمد:2379-3708
DOI:10.1172/jci.insight.143465