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Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0
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Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 32207

Special Issue Editor

Prof. Dr. Lubov Timchenko

E-Mail Website
Guest Editor
Department of Pediatrics, Division of Neurology, Cincinnati Children’s Hospital, Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
Interests: genetic diseases with unstable expansions; RNA-binding proteins; molecular biology and biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics".

Myotonic dystrophies (DM) type 1 and type 2 are complex genetic diseases affecting many tissues, including the skeletal muscle, heart, and brain. DM1 and DM2 are caused by unstable expansions of CTG (DM1) and CCTG (DM2) repeats. Both diseases do not have a cure. The molecular studies of DM identified the major mechanisms for these disorders, associated with the toxic effects of the mutant RNAs, containing long CUG and CCUG repeats. However, the mutant RNAs in DM1 and DM2 might affect additional intracellular pathways, increasing the complexity of molecular pathogenesis. This Special Issue will summarize findings describing the molecular mechanisms of DM1 and DM2 and will discuss how these advances can be used for the development of the clinical studies in DM1 and DM2.  

Prof. Lubov Timchenko
Guest Editor

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 474 KiB  
Editorial
Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics
by Lubov Timchenko
Int. J. Mol. Sci. 2022, 23(19), 11954; https://doi.org/10.3390/ijms231911954 - 8 Oct 2022
Cited by 2 | Viewed by 2110
Abstract
Current studies concerning myotonic dystrophy type 1 (DM1) are in the process of transitioning from molecular investigations to preclinical and clinical trials [...] Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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Research

Jump to: Editorial, Review

20 pages, 2546 KiB  
Article
DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus
by Brigitte Potier, Louison Lallemant, Sandrine Parrot, Aline Huguet-Lachon, Geneviève Gourdon, Patrick Dutar and Mário Gomes-Pereira
Int. J. Mol. Sci. 2022, 23(2), 592; https://doi.org/10.3390/ijms23020592 - 6 Jan 2022
Cited by 6 | Viewed by 3700
Abstract
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show [...] Read more.
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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Review

Jump to: Editorial, Research

17 pages, 1497 KiB  
Review
Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2
by Lubov Timchenko
Int. J. Mol. Sci. 2022, 23(18), 10491; https://doi.org/10.3390/ijms231810491 - 10 Sep 2022
Cited by 10 | Viewed by 3158
Abstract
Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 [...] Read more.
Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients’ cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1). Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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14 pages, 663 KiB  
Review
Targeting Myotonic Dystrophy Type 1 with Metformin
by Mikel García-Puga, Ander Saenz-Antoñanzas, Ander Matheu and Adolfo López de Munain
Int. J. Mol. Sci. 2022, 23(5), 2901; https://doi.org/10.3390/ijms23052901 - 7 Mar 2022
Cited by 13 | Viewed by 5532
Abstract
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently [...] Read more.
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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17 pages, 623 KiB  
Review
Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies
by Jorge Espinosa-Espinosa, Anchel González-Barriga, Arturo López-Castel and Rubén Artero
Int. J. Mol. Sci. 2022, 23(3), 1441; https://doi.org/10.3390/ijms23031441 - 27 Jan 2022
Cited by 5 | Viewed by 5024
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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23 pages, 658 KiB  
Review
Molecular and Clinical Implications of Variant Repeats in Myotonic Dystrophy Type 1
by Stojan Peric, Jovan Pesovic, Dusanka Savic-Pavicevic, Vidosava Rakocevic Stojanovic and Giovanni Meola
Int. J. Mol. Sci. 2022, 23(1), 354; https://doi.org/10.3390/ijms23010354 - 29 Dec 2021
Cited by 15 | Viewed by 2938
Abstract
Myotonic dystrophy type 1 (DM1) is one of the most variable monogenic diseases at phenotypic, genetic, and epigenetic level. The disease is multi-systemic with the age at onset ranging from birth to late age. The underlying mutation is an unstable expansion of CTG [...] Read more.
Myotonic dystrophy type 1 (DM1) is one of the most variable monogenic diseases at phenotypic, genetic, and epigenetic level. The disease is multi-systemic with the age at onset ranging from birth to late age. The underlying mutation is an unstable expansion of CTG repeats in the DMPK gene, varying in size from 50 to >1000 repeats. Generally, large expansions are associated with an earlier age at onset. Additionally, the most severe, congenital DM1 form is typically associated with local DNA methylation. Genetic variability of DM1 mutation is further increased by its structural variations due to presence of other repeats (e.g., CCG, CTC, CAG). These variant repeats or repeat interruptions seem to confer an additional level of epigenetic variability since local DNA methylation is frequently associated with variant CCG repeats independently of the expansion size. The effect of repeat interruptions on DM1 molecular pathogenesis is not investigated enough. Studies on patients indicate their stabilizing effect on DMPK expansions because no congenital cases were described in patients with repeat interruptions, and the age at onset is frequently later than expected. Here, we review the clinical relevance of repeat interruptions in DM1 and genetic and epigenetic characteristics of interrupted DMPK expansions based on patient studies. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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13 pages, 1209 KiB  
Review
Disrupting the Molecular Pathway in Myotonic Dystrophy
by Xiaomeng Xing, Anjani Kumari, Jake Brown and John David Brook
Int. J. Mol. Sci. 2021, 22(24), 13225; https://doi.org/10.3390/ijms222413225 - 8 Dec 2021
Cited by 6 | Viewed by 3849
Abstract
Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains [...] Read more.
Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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15 pages, 1919 KiB  
Review
Cardiac Pathology in Myotonic Dystrophy Type 1
by Mani S. Mahadevan, Ramesh S. Yadava and Mahua Mandal
Int. J. Mol. Sci. 2021, 22(21), 11874; https://doi.org/10.3390/ijms222111874 - 2 Nov 2021
Cited by 12 | Viewed by 4475
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics 2.0)
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