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 MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 1876-1886 ◽  
Author(s):  
Michael Flower ◽  
Vilija Lomeikaite ◽  
Marc Ciosi ◽  
Sarah Cumming ◽  
Fernando Morales ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Association Study ◽  
Huntington’S Disease ◽  
Myotonic Dystrophy ◽  
Disease Onset ◽  
Repeat Expansion ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Exon 1

Abstract The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

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.

scholarly journals CTG-Repeat Detection in Primary Human Myoblasts of Myotonic Dystrophy Type 1

2021 ◽  
Vol 15 ◽  
Author(s):  
Stefan Hintze ◽  
Raphaela Mensel ◽  
Lisa Knaier ◽  
Benedikt Schoser ◽  
Peter Meinke
Keyword(s):  
Myotonic Dystrophy ◽  
Muscle Biopsy ◽  
Biopsy Specimen ◽  
Repeat Length ◽  
Model Systems ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Repeat Expansions ◽  
Ctg Repeat

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by unstable CTG-repeat expansions in the DMPK gene. Tissue mosaicism has been described for the length of these repeat expansions. The most obvious affected tissue is skeletal muscle, making it the first target for therapy development. To date there is no approved therapy despite some existing approaches. Thus, there is the demand to further advance therapeutic developments, which will in return require several well-characterized preclinical tools and model systems. Here we describe a modified method to identify the CTG-repeat length in primary human myoblasts isolated from DM1 patients that requires less genomic DNA and avoids radioactive labeling. Using this method, we show that primary human DM1 myoblast cultures represent a population of cells with different CTG-repeat length. Comparing DNA from the identical muscle biopsy specimen, the range of CTG-repeat length in the myoblast culture is within the same range of the muscle biopsy specimen. In conclusion, primary human DM1 myoblast cultures are a well-suited model to investigate certain aspects of the DM1 pathology. They are a useful platform to perform first-line investigations of preclinical therapies.

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
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