scholarly journals The Need for Establishing a Universal CTG Sizing Method in Myotonic Dystrophy Type 1

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 757 ◽  
Author(s):  
Alfonsina Ballester-Lopez ◽  
Ian Linares-Pardo ◽  
Emma Koehorst ◽  
Judit Núñez-Manchón ◽  
Guillem Pintos-Morell ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Accurate Determination ◽  
Disease Onset ◽  
Clinical Severity ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
Long Pcr ◽  
Ctg Expansion

The number of cytosine-thymine-guanine (CTG) repeats (‘CTG expansion size’) in the 3′untranslated region (UTR) region of the dystrophia myotonica-protein kinase (DMPK) gene is a hallmark of myotonic dystrophy type 1 (DM1), which has been related to age of disease onset and clinical severity. However, accurate determination of CTG expansion size is challenging due to its characteristic instability. We compared five different approaches (heat pulse extension polymerase chain reaction [PCR], long PCR-Southern blot [with three different primers sets—1, 2 and 3] and small pool [SP]-PCR) to estimate CTG expansion size in the progenitor allele as well as the most abundant CTG expansion size, in 15 patients with DM1. Our results indicated variability between the methods (although we found no overall differences between long PCR 1 and 2 and SP-PCR, respectively). While keeping in mind the limited sample size of our patient cohort, SP-PCR appeared as the most suitable technique, with an inverse significant correlation found between CTG expansion size of the progenitor allele, as determined by this method, and age of disease onset (r = −0.734, p = 0.016). Yet, in light of the variability of the results obtained with the different methods, we propose that an international agreement is needed to determine which is the most suitable method for assessing CTG expansion size in DM1.

scholarly journals Three-dimensional imaging in myotonic dystrophy type 1

2020 ◽  
Vol 6 (4) ◽  
pp. e484
Author(s):  
Alfonsina Ballester-Lopez ◽  
Judit Núñez-Manchón ◽  
Emma Koehorst ◽  
Ian Linares-Pardo ◽  
Miriam Almendrote ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Disease Onset ◽  
Three Dimensional ◽  
Minor Role ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Foci ◽  
Cytoplasmic Rna ◽  
Ctg Expansion

ObjectiveWe aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1).MethodsWe obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase (DMPK) expression and splicing alterations of MBNL1, insulin receptor, and sarcoplasmic reticulum Ca(2+)-ATPase 1.ResultsThree-dimensional analysis showed that RNA foci (nuclear and/or cytoplasmic) were present in 45%–100% of DM1-derived myoblasts we studied (range: 0–6 foci per cell). RNA foci represented <0.6% of the total myoblast nuclear volume. CTG expansion size was associated with the number of RNA foci per myoblast (r = 0.876 [95% confidence interval 0.222–0.986]) as well as with the number of cytoplasmic RNA foci (r = 0.943 [0.559–0.994]). Although MBNL1 colocalized with RNA foci in all DM1 myoblast cell lines, colocalization only accounted for 1% of total MBNL1 expression, with the absence of DM1 alternative splicing patterns. The number of RNA foci was associated with DMPK expression (r = 0.967 [0.079–0.999]). On the other hand, the number of cytoplasmic RNA foci was correlated with the age at disease onset (r = −0.818 [−0.979 to 0.019]).ConclusionsCTG expansion size modulates RNA foci number in myoblasts derived from patients with DM1. MBNL1 sequestration plays only a minor role in the pathobiology of the disease in these cells. Higher number of cytoplasmic RNA foci is related to an early onset of the disease, a finding that should be corroborated in future studies.

scholarly journals Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1321
Author(s):  
Alfonsina Ballester-Lopez ◽  
Emma Koehorst ◽  
Ian Linares-Pardo ◽  
Judit Núñez-Manchón ◽  
Miriam Almendrote ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Genetic Instability ◽  
Disease Onset ◽  
Clinical Manifestations ◽  
Preliminary Evidence ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Blood Leukocytes ◽  
Ctg Expansion

Myotonic Dystrophy type 1 (DM1) is characterized by a high genetic and clinical variability. Determination of the genetic variability in DM1 might help to determine whether there is an association between CTG (Cytosine-Thymine-Guanine) expansion and the clinical manifestations of this condition. We studied the variability of the CTG expansion (progenitor, mode, and longest allele, respectively, and genetic instability) in three tissues (blood, muscle, and tissue) from eight patients with DM1. We also studied the association of genetic data with the patients’ clinical characteristics. Although genetic instability was confirmed in all the tissues that we studied, our results suggest that CTG expansion is larger in muscle and skin cells compared with peripheral blood leukocytes. While keeping in mind that more research is needed in larger cohorts, we have provided preliminary evidence suggesting that the estimated progenitor CTG size in muscle could be potentially used as an indicator of age of disease onset and muscle function impairment.

scholarly journals Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

2019 ◽  
Vol 20 (16) ◽  
pp. 4017 ◽  
Author(s):  
Kaalak Reddy ◽  
Jana R. Jenquin ◽  
John D. Cleary ◽  
J. Andrew Berglund
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Disease Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Toxicity ◽  
Complex Mechanisms ◽  
Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

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 Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1

2010 ◽  
Vol 43 (6) ◽  
pp. 149-156 ◽  
Author(s):  
Kyoko Itoh ◽  
Maki Mitani ◽  
Kunihiko Kawamoto ◽  
Naonobu Futamura ◽  
Itaru Funakawa ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Regional Differences ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
The Brain

Associations between grip strength, myotonia and CTG expansion in myotonic dystrophy type 1

2017 ◽  
Vol 27 ◽  
pp. S227
Author(s):  
J. Hogrel ◽  
G. Ollivier ◽  
I. Ledoux ◽  
L. Hébert ◽  
B. Eymard ◽  
...  
Keyword(s):  
Grip Strength ◽  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Expansion

scholarly journals Inhibition of Postn Rescues Myogenesis Defects in Myotonic Dystrophy Type 1 Myoblast Model

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaopeng Shen ◽  
Zhongxian Liu ◽  
Chunguang Wang ◽  
Feng Xu ◽  
Jingyi Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Myotonic Dystrophy ◽  
Cell Model ◽  
Neutralizing Antibody ◽  
Underlying Mechanism ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
Myoblast Cells

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease caused by expanded CTG repeats in the 3′ untranslated region (3′UTR) of the DMPK gene. The myogenesis process is defective in DM1, which is closely associated with progressive muscle weakness and wasting. Despite many proposed explanations for the myogenesis defects in DM1, the underlying mechanism and the involvement of the extracellular microenvironment remained unknown. Here, we constructed a DM1 myoblast cell model and reproduced the myogenesis defects. By RNA sequencing (RNA-seq), we discovered that periostin (Postn) was the most significantly upregulated gene in DM1 myogenesis compared with normal controls. This difference in Postn was confirmed by real-time quantitative PCR (RT-qPCR) and western blotting. Moreover, Postn was found to be significantly upregulated in skeletal muscle and myoblasts of DM1 patients. Next, we knocked down Postn using a short hairpin RNA (shRNA) in DM1 myoblast cells and found that the myogenesis defects in the DM1 group were successfully rescued, as evidenced by increases in the myotube area, the fusion index, and the expression of myogenesis regulatory genes. Similarly, Postn knockdown in normal myoblast cells enhanced myogenesis. As POSTN is a secreted protein, we treated the DM1 myoblast cells with a POSTN-neutralizing antibody and found that DM1 myogenesis defects were successfully rescued by POSTN neutralization. We also tested the myogenic ability of myoblasts in the skeletal muscle injury mouse model and found that Postn knockdown improved the myogenic ability of DM1 myoblasts. The activity of the TGF-β/Smad3 pathway was upregulated during DM1 myogenesis but repressed when inhibiting Postn with a Postn shRNA or a POSTN-neutralizing antibody, which suggested that the TGF-β/Smad3 pathway might mediate the function of Postn in DM1 myogenesis. These results suggest that Postn is a potential therapeutical target for the treatment of myogenesis defects in DM1.

scholarly journals Direct Haplotyping-Based Noninvasive Prenatal Test for Myotonic Dystrophy Type 1 with Large CTG Expansion

2020 ◽  
Vol 66 (4) ◽  
pp. 614-615
Author(s):  
Jee-Soo Lee ◽  
Kyung Bok Lee ◽  
Han Song ◽  
ChoongHyun Sun ◽  
Man Jin Kim ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Prenatal Test ◽  
Ctg Expansion

scholarly journals Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Dušanka Savić Pavićević ◽  
Jelena Miladinović ◽  
Miloš Brkušanin ◽  
Saša Šviković ◽  
Svetlana Djurica ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Molecular Genetics ◽  
Myotonic Dystrophy ◽  
Age At Onset ◽  
Gender Effect ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
Parental Gender

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of theDMPKgene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

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