Coincident Trinucleotide Repeat Expansions in a Patient With Myotonic Dystrophy Type 1 and Spinocerebellar Ataxia

2008 ◽  
Vol 10 (1) ◽  
pp. 22-23 ◽  
Author(s):  
Stephen J Kolb ◽  
John T Kissel
Keyword(s):  
Myotonic Dystrophy ◽  
Spinocerebellar Ataxia ◽  
Trinucleotide Repeat ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Repeat Expansions

scholarly journals Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

2019 ◽  
Vol 116 (50) ◽  
pp. 25203-25213 ◽  
Author(s):  
Ariadna Bargiela ◽  
Maria Sabater-Arcis ◽  
Jorge Espinosa-Espinosa ◽  
Miren Zulaica ◽  
Adolfo Lopez de Munain ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Muscle Area ◽  
In Vivo Models

Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.

scholarly journals Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1

2019 ◽  
Vol 116 (18) ◽  
pp. 8709-8714 ◽  
Author(s):  
JuYeon Lee ◽  
Yugang Bai ◽  
Ullas V. Chembazhi ◽  
Shaohong Peng ◽  
Kevin Yum ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Cell Penetrating Peptides ◽  
Cell Permeability ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Multivalent Ligands ◽  
Biological Studies ◽  
Cell Penetrating

Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1Drosophilawas also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.

scholarly journals Structure and Dynamics of RNA Repeat Expansions That Cause Huntington’s Disease and Myotonic Dystrophy Type 1

Biochemistry ◽  
2017 ◽  
Vol 56 (27) ◽  
pp. 3463-3474 ◽  
Author(s):  
Jonathan L. Chen ◽  
Damian M. VanEtten ◽  
Matthew A. Fountain ◽  
Ilyas Yildirim ◽  
Matthew D. Disney
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Structure And Dynamics ◽  
Repeat Expansions

scholarly journals Simple Repeat-Primed PCR Analysis of the Myotonic Dystrophy Type 1 Gene in a Clinical Diagnostics Environment

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Philippa A. Dryland ◽  
Elaine Doherty ◽  
Jennifer M. Love ◽  
Donald R. Love
Keyword(s):  
Myotonic Dystrophy ◽  
Trinucleotide Repeat ◽  
Neuromuscular Disorder ◽  
Clinical Diagnostics ◽  
Pcr Analysis ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Diagnostic Laboratory ◽  
Ctg Repeat

Myotonic dystrophy type 1 is an autosomal dominant neuromuscular disorder that is caused by the expansion of a CTG trinucleotide repeat in the DMPK gene. The confirmation of a clinical diagnosis of DM-1 usually involves PCR amplification of the CTG repeat-containing region and subsequent sizing of the amplification products in order to deduce the number of CTG repeats. In the case of repeat hyperexpansions, Southern blotting is also used; however, the latter has largely been superseded by triplet repeat-primed PCR (TP-PCR), which does not yield a CTG repeat number but nevertheless provides a means of stratifying patients regarding their disease severity. We report here a combination of forward and reverse TP-PCR primers that allows for the simple and effective scoring of both the size of smaller alleles and the presence or absence of expanded repeat sequences. In addition, the CTG repeat-containing TP-PCR forward primer can target both the DM-1 and Huntington disease genes, thereby streamlining the work flow for confirmation of clinical diagnoses in a diagnostic laboratory.

scholarly journals Transcriptome Analysis in a Primary Human Muscle Cell Differentiation Model for Myotonic Dystrophy Type 1

2021 ◽  
Vol 22 (16) ◽  
pp. 8607
Author(s):  
Vanessa Todorow ◽  
Stefan Hintze ◽  
Alastair R. W. Kerr ◽  
Andreas Hehr ◽  
Benedikt Schoser ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Myotonic Dystrophy ◽  
Therapeutic Interventions ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Gene Set Enrichment ◽  
Repeat Expansions ◽  
Differentiation Stage ◽  
Term Analysis

Myotonic dystrophy type 1 (DM1) is caused by CTG-repeat expansions leading to a complex pathology with a multisystemic phenotype that primarily affects the muscles and brain. Despite a multitude of information, especially on the alternative splicing of several genes involved in the pathology, information about additional factors contributing to the disease development is still lacking. We performed RNAseq and gene expression analyses on proliferating primary human myoblasts and differentiated myotubes. GO-term analysis indicates that in myoblasts and myotubes, different molecular pathologies are involved in the development of the muscular phenotype. Gene set enrichment for splicing reveals the likelihood of whole, differentiation stage specific, splicing complexes that are misregulated in DM1. These data add complexity to the alternative splicing phenotype and we predict that it will be of high importance for therapeutic interventions to target not only mature muscle, but also satellite cells.

scholarly journals Novel Heat Pulse Extension-PCR–Based Method for Detection of Large CTG-Repeat Expansions in Myotonic Dystrophy Type 1

2013 ◽  
Vol 15 (1) ◽  
pp. 110-115 ◽  
Author(s):  
Arto K. Orpana ◽  
Tho H. Ho ◽  
Katariina Alagrund ◽  
Maaret Ridanpää ◽  
Kristiina Aittomäki ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Heat Pulse ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Repeat Expansions ◽  
Ctg Repeat

scholarly journals Syncope and hyperCKemia as minimal manifestations of short CTG repeat expansions in myotonic dystrophy type 1

2015 ◽  
Vol 34 (5) ◽  
pp. 361.e1-361.e4 ◽  
Author(s):  
Josef Finsterer ◽  
Claudia Stöllberger ◽  
Martin Gencik ◽  
Romana Höftberger ◽  
Jasmin Rahimi ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Repeat Expansions ◽  
Ctg Repeat

scholarly journals High Throughput Screening for Expanded CTG repeats in Myotonic Dystrophy Type 1 Using Melt Curve Analysis

2021 ◽  
Author(s):  
Russell J Butterfield ◽  
Carina Imburgia ◽  
Katie Mayne ◽  
Tara Newcomb ◽  
Diane M Dunn ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
High Throughput ◽  
Curve Analysis ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Melt Curve Analysis ◽  
Ctg Repeats ◽  
Repeat Expansions ◽  
Ctg Repeat

ABSTRACTBackgroundMyotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often non-specific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and cost prohibitive for population surveys.MethodsHere, we present a high throughput, low-cost screening tool for CTG repeat expansions using TP-PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye.ResultsWe determined that multimodal melt profiles from the TP-PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri-modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles.ConclusionWe demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large-scale testing programs such as population studies and newborn screening programs.

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