Special Issue "Diagnosis, Pathomechanisms, Treatment and Management of Myotonic Dystrophy"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: 1 December 2021.

Special Issue Editors

Dr. Gisela Nogales-Gadea
E-Mail Website
Guest Editor
Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain
Interests: neuromuscular diseases; skeletal muscle physiology; skeletal muscle fibers; muscle proteins; genetics; transcriptomics; molecular treatments
Dr. Mònica Suelves
E-Mail Website
Guest Editor
Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain
Interests: myogenesis; skeletal muscle tissue; epigenetic regulation; DNA (de)methylation; HDACs; muscle pathologies

Special Issue Information

Dear Colleagues,

The available knowledge on Myotonic Dystrophy type I (DM1) increases every day. However, the complex mechanisms that are involved in this rare disease are still under investigation. The primary cause is clear, a genetic expansion in the 3’ UTR region of DMPK gene, in which a CTG repeat is found over 50 times in DM1 patients. From there, the pathomechanisms that have been studied, which are triggered by this genetic expansion, are extremely diverse: nuclear accumulation of expanded DMPK transcripts, entrapment of proteins, splicing alterations, changes in methylation, and altered expression of the genes surrounding the DMPK gene, among others. In the clinical side the scenario is also complex, with heterogeneous symptomatic manifestation and only symptomatic treatment available. Therefore, we invite other research colleagues to contribute to this special issue that aims to keep moving forward in the research for DM1.

Dr. Gisela Nogales-Gadea
Dr. Mònica Suelves
Guest Editors

Manuscript Submission Information

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Keywords

  • diagnosis
  • molecular mechanisms
  • biomarkers
  • antisense oligonucleotides
  • gene edition
  • patient management
  • personalized medicine

Published Papers (3 papers)

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Research

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Article
Characterization of RAN Translation and Antisense Transcription in Primary Cell Cultures of Patients with Myotonic Dystrophy Type 1
J. Clin. Med. 2021, 10(23), 5520; https://doi.org/10.3390/jcm10235520 (registering DOI) - 25 Nov 2021
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Abstract
Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our [...] Read more.
Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods. Full article
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Article
Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles
J. Clin. Med. 2021, 10(17), 3934; https://doi.org/10.3390/jcm10173934 - 31 Aug 2021
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Abstract
Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, [...] Read more.
Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguous CNBP alleles containing uninterrupted CCTG repeats in the range between 32 and 42 repeats. While these grey-zone alleles are most likely not pathogenic themselves, since other pathogenic mutations were identified and particular family structures did not support their pathogenic role, they were found to be unstable during intergenerational transmission. On the other hand, there was no observable general microsatellite instability in the genome of the carriers of these alleles. Our results further refine the division of CNBP CCTG repeat alleles into two major groups, i.e., interrupted and uninterrupted alleles. Both interrupted and uninterrupted alleles with up to approximately 30 CCTG repeats were shown to be generally stable during intergenerational transmission, while intergenerational as well as somatic instability seems to gradually increase in uninterrupted alleles with tract length growing above this threshold. Full article
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Review

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Review
The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I
J. Clin. Med. 2020, 9(12), 3939; https://doi.org/10.3390/jcm9123939 - 04 Dec 2020
Cited by 4 | Viewed by 792
Abstract
MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most [...] Read more.
MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most frequent autosomal dominant muscle dystrophy in adults, with an estimated prevalence of 1:8000. DM1 symptoms include muscle weakness, myotonia, respiratory failure, cardiac conduction defects, cataracts, and endocrine disturbances. Patients display heterogeneity in both age of onset and disease manifestation. No treatment or cure currently exists for DM1, which shows the necessity for a biomarker that can predict disease progression, providing the opportunity to implement preventative measures before symptoms arise. In the past two decades, extensive research has been conducted in the miRNA expression profiles of DM1 patients and their biomarker potential. Here we review the current state of the field with a tissue-specific focus, given the multi-systemic nature of DM1 and the intracellular signaling role of miRNAs. Full article
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