scholarly journals Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease

2013 ◽  
Vol 10 (88) ◽  
pp. 20130605 ◽  
Author(s):  
Catherine F. Higham ◽  
Darren G. Monckton
Keyword(s):  
Huntington Disease ◽  
Disease Onset ◽  
Repeat Length ◽  
Effective Length ◽  
Mutation Rates ◽  
Extended Model ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Somatic Instability

More than 20 human genetic diseases are associated with inheriting an unstable expanded DNA simple sequence tandem repeat, for example, CTG (cytosine–thymine–guanine) repeats in myotonic dystrophy type 1 (DM1) and CAG (cytosine–adenine–guanine) repeats in Huntington disease (HD). These sequences mutate by changing the number of repeats not just between generations, but also during the lifetime of affected individuals. Levels of somatic instability contribute to disease onset and progression but as changes are tissue-specific, age- and repeat length-dependent, interpretation of the level of somatic instability in an individual is confounded by these considerations. Mathematical models, fitted to CTG repeat length distributions derived from blood DNA, from a large cohort of DM1-affected or at risk individuals, have recently been used to quantify inherited repeat lengths and mutation rates. Taking into account age, the estimated mutation rates are lower than predicted among individuals with small alleles (inherited repeat lengths less than 100 CTGs), suggesting that these rates may be suppressed at the lower end of the disease-causing range. In this study, we propose that a length-specific effect operates within this range and tested this hypothesis using a model comparison approach. To calibrate the extended model, we used data derived from blood DNA from DM1 individuals and, for the first time, buccal DNA from HD individuals. In a novel application of this extended model, we identified individuals whose effective repeat length, with regards to somatic instability, is less than their actual repeat length. A plausible explanation for this distinction is that the expanded repeat tract is compromised by interruptions or other unusual features. We quantified effective length for a large cohort of DM1 individuals and showed that effective length better predicts age of onset than inherited repeat length, thus improving the genotype–phenotype correlation. Under the extended model, we removed some of the bias in mutation rates making them less length-dependent. Consequently, rates adjusted in this way will be better suited as quantitative traits to investigate cis- or trans -acting modifiers of somatic mosaicism, disease onset and progression.

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.

Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1

Neurology ◽  
2004 ◽  
Vol 62 (7) ◽  
pp. 1081-1089 ◽  
Author(s):  
E. L. Logigian ◽  
R. T. Moxley ◽  
C. L. Blood ◽  
C. A. Barbieri ◽  
W. B. Martens ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Repeat Length ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeat

P.35Parental repeat length instability in myotonic dystrophy type 1 pre- and protomutations

2019 ◽  
Vol 29 ◽  
pp. S51
Author(s):  
I. Joosten ◽  
D. Hellebrekers ◽  
B. de Greef ◽  
H. Smeets ◽  
C. de Die-Smulders ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Repeat Length ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type

Somatic instability of CTG repeats in the cerebellum of myotonic dystrophy type 1

2013 ◽  
Vol 48 (1) ◽  
pp. 105-108 ◽  
Author(s):  
Kenji Jinnai ◽  
Maki Mitani ◽  
Naonobu Futamura ◽  
Kunihiko Kawamoto ◽  
Itaru Funakawa ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Ctg Repeats ◽  
Somatic Instability

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.

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