Molecular and Clinical Implications of Variant Repeats in Myotonic Dystrophy Type 1.
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ABSTRACT:
SUBMITTER: Peric S
PROVIDER: S-EPMC8745394 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective:We tested the hypothesis that variant repeat interruptions (RIs) within the DMPK CTG repeat tract lead to milder symptoms compared with pure repeats (PRs) in myotonic dystrophy type 1 (DM1). Methods:We evaluated motor, neurocognitive, and behavioral outcomes in a group of 6 participants with DM1 with RI compared with a case-matched sample of 12 participants with DM1 with PR and a case-matched sample of 12 unaffected healthy comparison participants (UA). Results:In every measure, the RI participants were intermediate between UA and PR participants. For muscle strength, the RI group was significantly less impaired than the PR group. For measures of Full Scale IQ, depression, and sleepiness, all 3 groups were significantly different from each other with UA > RI > PR in order of impairment. The RI group was different from unaffected, but not significantly different from PR (UA > RI = PR) in apathy and working memory. Finally, in finger tapping and processing speed, RI did not differ from UA comparisons, but PR had significantly lower scores than the UA comparisons (UA = RI > PR). Conclusions:Our results support the notion that patients affected by DM1 with RI demonstrate a milder phenotype with the same pattern of deficits as those with PR indicating a similar disease process.
| S-EPMC7428360 | biostudies-literature
Project description:ObjectiveTo assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention.MethodsAdult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory-fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions.ResultsVR interruptions were detectable in 21/250 patients (8.4%)-12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions.ConclusionsThe presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention.Trial registration informationClinicalTrials.gov NCT02118779.
| S-EPMC8054967 | biostudies-literature
Project description:Tracks containing CUG repeats are abundant in human gene transcripts. Their biological role includes modulation of pre-mRNA splicing, mRNA transport and regulation of translation. Expanded forms of CUG runs are associated with pathogenesis of several neurodegenerative diseases, including myotonic dystrophy type 1. We have analysed two crystal structures of RNA duplexes containing the CUG repeats: G(CUG)(2)C and (CUG)(6). The first of the structures, analysed at 1.23 A resolution, is of an oligomer designed by us. The second model was obtained after 'detwinning' the 1.58 A X-ray data previously deposited in the PDB. The RNA duplexes are in the A-form in which all the C-G pairs form Watson-Crick interactions while all the uridine pairs can be described as U*U cis wobble having only one hydrogen bond between the bases. The residue, which accepts the H-bond, is inclined towards the minor groove. This previously unreported base pairing can be described as 'stretched U-U wobble'. The regular hydrogen-bonding pattern of interactions with the solvent, the electrostatic charge distribution and surface features indicate the ligand binding potential of the CUG tracks.
| S-EPMC2709583 | biostudies-literature
Project description:Expansion of RNA CUG repeats causes myotonic dystrophy type 1 (DM1). Once transcribed, the expanded CUG repeats strongly attract muscleblind-like 1 (MBNL1) proteins and disturb their functions in cells. Because of its unique structural form, expanded RNA CUG repeats are prospective drug targets, where small molecules can be utilized to target RNA CUG repeats to inhibit MBNL1 binding and ameliorate DM1-associated defects. In this contribution, we developed two physics-based dynamic docking approaches (DynaD and DynaD/Auto) and applied them to nine small molecules known to specifically target RNA CUG repeats. While DynaD uses a distance-based reaction coordinate to study the binding phenomenon, DynaD/Auto combines results of umbrella sampling calculations performed on 1 × 1 UU internal loops and AutoDock calculations to efficiently sample the energy landscape of binding. Predictions are compared with experimental data, displaying a positive correlation with correlation coefficient (R) values of 0.70 and 0.81 for DynaD and DynaD/Auto, respectively. Furthermore, we found that the best correlation was achieved with MM/3D-RISM calculations, highlighting the importance of solvation in binding calculations. Moreover, we detected that DynaD/Auto performed better than DynaD because of the use of prior knowledge about the binding site arising from umbrella sampling calculations. Finally, we developed dendrograms to present how bound states are connected to each other in a binding process. Results are exciting, as DynaD and DynaD/Auto will allow researchers to utilize two novel physics-based and computer-aided drug-design methodologies to perform in silico calculations on drug-like molecules aiming to target complex RNA loops.
| S-EPMC9822796 | biostudies-literature
Project description:BackgroundFew adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1).ObjectiveThe goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length.MethodsNeuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial volume (ICV).ResultsICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter.ConclusionsSmaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers.
| S-EPMC7480174 | biostudies-literature
Project description:Myotonic Dystrophy type 1 (DM1) is a multisystemic disease caused by toxic RNA from a DMPK gene carrying an expanded (CTG•CAG)n repeat. Promising strategies for treatment of DM1 patients are currently being tested. These include antisense oligonucleotides and drugs for elimination of expanded RNA or prevention of aberrant binding to RNP proteins. A significant hurdle for preclinical development along these lines is efficient systemic delivery of compounds across endothelial and target cell membranes. It has been reported that DM1 patients show elevated levels of markers of muscle damage or loss of sarcolemmal integrity in their serum and that splicing of dystrophin, an essential protein for muscle membrane structure, is abnormal. Therefore, we studied cell membrane integrity in DM1 mouse models commonly used for preclinical testing. We found that membranes in skeletal muscle, heart and brain were impermeable to Evans Blue Dye. Creatine kinase levels in serum were similar to those in wild type mice and expression of dystrophin protein was unaffected. Also in patient muscle biopsies cell surface expression of dystrophin was normal and calcium-positive fibers, indicating elevated intracellular calcium levels, were only rarely seen. Combined, our findings indicate that cells in DM1 tissues do not display compromised membrane integrity. Hence, the cell membrane is a barrier that must be overcome in future work towards effective drug delivery in DM1 therapy.
| S-EPMC4370802 | biostudies-literature
Project description:Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
| S-EPMC5964235 | biostudies-literature
Project description: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 the DMPK gene, 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.
| S-EPMC3613064 | biostudies-literature
Project description:IntroductionMyotonic dystrophy type 2 (DM2) is a rare, multisystemic, autosomal dominant disease with highly variable clinical presentation. DM2 is considered to be highly underdiagnosed.ObjectiveThe aim of this study was to determine which symptoms, signs, and diagnostic findings in patients referred to neurological outpatient units are the most indicative to arouse suspicion of DM2. We tried to make a useful and easy-to-administer clinical scoring system for early diagnosis of DM2-DM2 early diagnosis score (DM2-EDS).Patients and methodsTwo hundred ninety-one patients with a clinical suspicion of DM2 were included: 69 were genetically confirmed to have DM2, and 222 patients were DM2 negative. Relevant history, neurological, and paraclinical data were obtained from the electronic medical records.ResultsThe following parameters appeared as significant predictors of DM2 diagnosis: cataracts (beta = 0.410, p < 0.001), myotonia on needle EMG (beta = 0.298, p < 0.001), hand tremor (beta = 0.211, p = 0.001), positive family history (beta = 0.171, p = 0.012), and calf hypertrophy (beta = 0.120, p = 0.043). In the final DM2-EDS, based on the beta values, symptoms were associated with the following values: cataracts (present 3.4, absent 0), myotonia (present 2.5, absent 0), tremor (present 1.7, absent 0), family history (positive 1.4, negative 0), and calf hypertrophy (present 1.0, absent 0). A cut-off value on DM2-EDS of 3.25 of maximum 10 points had a sensitivity of 84% and specificity of 81% to diagnose DM2.ConclusionSignificant predictors of DM2 diagnosis in the neurology outpatient unit were identified. We made an easy-to-administer DM2-EDS score for early diagnosis of DM2.
| S-EPMC9925479 | biostudies-literature
Project description:An expanded CUG repeat transcript (CUG(exp)) is the causative agent of myotonic dystrophy type 1 (DM1) by sequestering muscleblind-like 1 protein (MBNL1), a regulator of alternative splicing. On the basis of a ligand (1) that was previously reported to be active in an in vitro assay, we present the synthesis of a small library containing 10 dimeric ligands (4-13) that differ in length, composition, and attachment point of the linking chain. The oligoamino linkers gave a greater gain in affinity for CUG RNA and were more effective when compared to oligoether linkers. The most potent in vitro ligand (9) was shown to be aqueous-soluble and both cell- and nucleus-permeable, displaying almost complete dispersion of MBNL1 ribonuclear foci in a DM1 cell model. Direct evidence for the bioactivity of 9 was observed in its ability to disperse ribonuclear foci in individual live DM1 model cells using time-lapse confocal fluorescence microscopy.
| S-EPMC3925341 | biostudies-literature