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

Rao, Ashish N.; Campbell, Hannah M.; Guan, Xiangnan; Word, Tarah A.; Wehrens, Xander H.T.; Xia, Zheng; Cooper, Thomas A.

doi:10.1172/jci.insight.143465

Cited by 12 publications

(11 citation statements)

References 73 publications

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“…Due to its size of 95bp, inclusion of exon 9 results in a frameshift that produces an alternative C-terminus in MBNL2, removing a PEST degradation domain in the C-terminus encoded by the mRNA that excludes exon 9. We also found that inclusion of Mbnl2 exon 6 and exon 9 and MBNL2 protein levels are significantly increased in our inducible DM1 heart mouse model (CUG960) that expresses an mRNA containing 960 CUG repeats in the context of human DMPK ( 25 ), indicating that the compensatory mechanism might also be active in DM1 tissues.…”

Section: Introductionsupporting

confidence: 58%

“…Thus, we were curious to investigate if the compensatory mechanism also occurs in tissues expressing CUGexp RNA. To do so, we used a recently generated a dox-inducible DM1 heart mouse model (Figure 7A ), TREDT960I/MHCrtTA (CUG960), that expresses 960 interrupted CUG repeats in the context of human DMPK and recapitulates the electrophysiological and molecular cardiac features of DM1 ( 25 ). To test if the inclusion of Mbnl2 exon 6 and exon 9 and MBNL2 protein levels are increased in heart tissue from these mice, we induced the CUG960 RNA using 2 g dox/kg chow starting at postnatal day 1 and harvested the hearts at eight weeks of age.…”

Section: Resultsmentioning

confidence: 99%

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Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function

Nitschke

Miller

et al. 2023

Nucleic Acids Research

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Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while the inclusion of Mbnl2 exon 9 shifts the reading frame to an alternative C-terminus. We show that the C-terminus lacking exon 9 contains a PEST domain which causes proteasomal degradation. Loss of MBNL1 increases the inclusion of exon 9, resulting in an alternative C-terminus lacking the PEST domain and the increase of MBNL2. We further find that the compensatory mechanism is active in a mouse DM1 model. Together, this study uncovers the compensatory mechanism by which loss of MBNL1 upregulates its paralog MBNL2 and highlights a potential role of the compensatory mechanism in DM1.

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Section: Introductionsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function

Nitschke

Miller

et al. 2023

Nucleic Acids Research

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“…RNA-Seq from heart samples in this model revealed gene expression and AS changes in ion transport genes associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with the RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from this model, potentially contributing to the observed arrhythmogenic phenotypes [62].…”

Section: Omics Studies In the Heartsupporting

confidence: 85%

“…Recently, a new mouse model has been reported, with inducible expression of human DMPK exons 11-15 carrying 960 interrupted CTG repeats in cardiomyocytes [62]. RNA-Seq from heart samples in this model revealed gene expression and AS changes in ion transport genes associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling.…”

Section: Omics Studies In the Heartmentioning

confidence: 99%

Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies

Espinosa-Espinosa

González-Barriga

López-Castel

et al. 2022

IJMS

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Omics studies are crucial to improve our understanding of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. Employing tissue samples and cell lines derived from patients and animal models, omics approaches have revealed the myriad alterations in gene and microRNA expression, alternative splicing, 3′ polyadenylation, CpG methylation, and proteins levels, among others, that contribute to this complex multisystem disease. In addition, omics characterization of drug candidate treatment experiments provides crucial insight into the degree of therapeutic rescue and off-target effects that can be achieved. Finally, several innovative technologies such as single-cell sequencing and artificial intelligence will have a significant impact on future DM1 research.

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“…Recently, another inducible/reversible mouse model of RNA toxicity in DM1 (TREDT960I) was reported from the Cooper lab, with cardiac specific expression of an RNA with exons 11–15 of DMPK with 960 interrupted CUGs [ 113 ]. These mice show RNA foci and a multitude of RNA splicing defects, decreased expression of connexin-40, and had prolongation of the QRS and QT c intervals, but did not show the prolongation of the PR interval, progressive heart block or sudden death seen in individuals with DM1.…”

Section: Mouse Models Of Rna Toxicity In Dm1 With Cardiac Phenotypesmentioning

confidence: 99%

Cardiac Pathology in Myotonic Dystrophy Type 1

Mahadevan

Yadava

Mandal

2021

IJMS

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Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

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

Abstract: In this study, we developed and characterized a transgenic mouse model for studying the cardiac pathogenesis of myotonic dystrophy type 1

Cited by 12 publications

References 73 publications

Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function

Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function

Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies

Cardiac Pathology in Myotonic Dystrophy Type 1

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