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Cell Reports Sep 2023Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays...
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.
Topics: Humans; Amyotrophic Lateral Sclerosis; Gene Expression Regulation; Genes, Homeobox; Homeodomain Proteins; Muscle, Skeletal; Muscular Dystrophy, Facioscapulohumeral; Neurodegenerative Diseases; Nuclear Matrix-Associated Proteins; RNA-Binding Proteins
PubMed: 37703175
DOI: 10.1016/j.celrep.2023.113120 -
Nature Communications Sep 2023The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein...
The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1's role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.
Topics: Animals; Mice; Chromatin; Epigenomics; Gene Silencing; Genes, Homeobox; Muscular Dystrophy, Facioscapulohumeral; Chromosomal Proteins, Non-Histone
PubMed: 37749075
DOI: 10.1038/s41467-023-40992-6 -
Acta Myologica : Myopathies and... 2023Massive parallel sequencing methods, such as exome, genome, and targeted DNA sequencing, have aided molecular diagnosis of genetic diseases in the last 20 years.... (Review)
Review
Massive parallel sequencing methods, such as exome, genome, and targeted DNA sequencing, have aided molecular diagnosis of genetic diseases in the last 20 years. However, short-read sequencing methods still have several limitations, such inaccurate genome assembly, the inability to detect large structural variants, and variants located in hard-to-sequence regions like highly repetitive areas. The recently emerged PacBio single-molecule real-time (SMRT) and Oxford nanopore technology (ONT) long-read sequencing (LRS) methods have been shown to overcome most of these technical issues, leading to an increase in diagnostic rate. LRS methods are contributing to the detection of repeat expansions in novel disease-causing genes (e.g., , and causing an Oculopharyngodistal myopathy or causing a Myopathy with rimmed ubiquitin-positive autophagic vacuolation), of structural variants (e.g., in ), and of single nucleotide variants in repetitive regions ( and ). Moreover, these methods have simplified the characterization of the D4Z4 repeats in , facilitating the diagnosis of Facioscapulohumeral muscular dystrophy (FSHD). We review recent studies that have used either ONT or PacBio SMRT sequencing methods and discuss different types of variants that have been detected using these approaches in individuals with neuromuscular disorders.
Topics: Humans; Sequence Analysis, DNA; Muscular Dystrophy, Facioscapulohumeral; Repetitive Sequences, Nucleic Acid; High-Throughput Nucleotide Sequencing
PubMed: 38406378
DOI: 10.36185/2532-1900-394 -
Molecular & Cellular Proteomics : MCP Aug 2023Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used...
Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; DO) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of "older" less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2'-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Proteome; Proteomics; Homeodomain Proteins; Myoblasts; Muscle, Skeletal
PubMed: 37353005
DOI: 10.1016/j.mcpro.2023.100605 -
European Heart Journal Dec 2023Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but...
BACKGROUND AND AIMS
Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants.
METHODS
Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC).
RESULTS
Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09).
CONCLUSIONS
Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.
Topics: Humans; Male; Female; Middle Aged; X-Linked Emery-Dreifuss Muscular Dystrophy; Retrospective Studies; Arrhythmias, Cardiac; Heart Diseases; Muscular Dystrophy, Emery-Dreifuss; Heart Failure; Mutation
PubMed: 37639473
DOI: 10.1093/eurheartj/ehad561 -
Science Advances Aug 2023Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular...
Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 () or CypD () in a δ-sarcoglycan () gene-deleted mouse model of MD, revealing that dystrophic mice lacking were partially protected from cell death and MD pathology. Dystrophic mice lacking both and together were almost completely protected from necrotic cell death and MD disease. This study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell death, suggesting a previously unrecognized therapeutic approach in MD and other necrotic diseases.
Topics: Animals; Mice; Muscular Dystrophies; Necrosis; Cell Death; Peptidyl-Prolyl Isomerase F; Disease Models, Animal
PubMed: 37624892
DOI: 10.1126/sciadv.adi2767 -
Biomolecules Nov 2023mice with a spontaneous mutation in exon 23 of the gene represent the most common model to investigate the pathophysiology of Duchenne muscular dystrophy (DMD). The...
mice with a spontaneous mutation in exon 23 of the gene represent the most common model to investigate the pathophysiology of Duchenne muscular dystrophy (DMD). The disease, caused by the lack of functional dystrophin, is characterized by irreversible impairment of muscle functions, with the diaphragm affected earlier and more severely than other skeletal muscles. We applied a label-free (LF) method and the more thorough tandem mass tag (TMT)-based method to analyze differentially expressed proteins in the diaphragm of 6-week-old mice. The comparison of both methods revealed 88 commonly changed proteins. A more in-depth analysis of the TMT-based method showed 953 significantly changed proteins, with 867 increased and 86 decreased in dystrophic animals (-value < 0.05, fold-change threshold: 1.5). Consequently, several dysregulated processes were demonstrated, including the immune response, fibrosis, translation, and programmed cell death. Interestingly, in the dystrophic diaphragm, we found a significant decrease in the expression of enzymes generating hydrogen sulfide (HS), suggesting that alterations in the metabolism of this gaseous mediator could modulate DMD progression, which could be a potential target for pharmacological intervention.
Topics: Animals; Mice; Mice, Inbred mdx; Diaphragm; Proteome; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Mice, Inbred C57BL
PubMed: 38002330
DOI: 10.3390/biom13111648 -
Journal of the American Heart... Aug 2023Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular... (Clinical Trial)
Clinical Trial
Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 (=0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; =0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank =0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.
Topics: Adult; Humans; Cardiomyopathies; Echocardiography, Doppler; Heart; Muscular Dystrophy, Duchenne; Prognosis; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function, Right
PubMed: 37581390
DOI: 10.1161/JAHA.122.027231 -
Neurotherapeutics : the Journal of the... Oct 2023Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. It is caused by mutations in the DMD gene, leading to reduced or absent... (Review)
Review
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. It is caused by mutations in the DMD gene, leading to reduced or absent expression of the dystrophin protein. Clinically, this results in loss of ambulation, cardiomyopathy, respiratory failure, and eventually death. In the past decades, the use of corticosteroids has slowed down the disease progression. More recently, the development of genetically mediated therapies has emerged as the most promising treatment for DMD. These strategies include exon skipping with antisense oligonucleotides, gene replacement therapy with adeno-associated virus, and gene editing with CRISPR (clustered regularly interspaced short palindromic repeats) technology. In this review, we highlight the most up-to-date therapeutic progresses in the field, with emphasis on past and recent experiences, as well as the latest clinical results of DMD micro-dystrophin gene therapy. Additionally, we discuss the lessons learned along the way and the challenges encountered, all of which have helped advance the field, with the potential to finally alleviate such a devastating disease.
Topics: Humans; Child; Muscular Dystrophy, Duchenne; Dystrophin; Gene Editing; Exons; Genetic Therapy
PubMed: 37673849
DOI: 10.1007/s13311-023-01423-y -
Journal of the American Heart... Nov 2023Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively...
Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0-50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age- and sex-matched healthy control cohort (n=50). Cardiovascular magnetic resonance markers, including 3-dimensional strain and fibrosis, were assessed for their respective association with major adverse cardiac events. Our results showed that markers of contractile performance were reduced across all muscular dystrophy groups. In particular, the dystrophinopathies cohort experienced reduced left ventricular (LV) ejection fraction and high burden of replacement fibrosis. Patients with type 1 myotonic dystrophy showed a 26.8% relative reduction in LV mass with corresponding reduction in chamber volumes. Eighty-two major adverse cardiac events occurred over a median follow-up of 5.2 years. Although LV ejection fraction was significantly associated with major adverse cardiac events (adjusted hazard ratio [aHR], 3.0 [95% CI, 1.4-6.4]) after adjusting for covariates, peak 3-dimensional strain amplitude demonstrated greater predictive value (minimum principal amplitude: aHR, 5.5 [95% CI, 2.5-11.9]; maximum principal amplitude: aHR, 3.3 [95% CI, 1.6-6.8]; circumferential amplitude: aHR, 3.4 [95% CI, 1.6-7.2]; longitudinal amplitude: aHR, 3.4 [95% CI, 1.7-6.9]; and radial strain amplitude: aHR, 3.0 [95% CI, 1.4-6.1]). Minimum principal strain yielded incremental prognostic value beyond LV ejection fraction for association with major adverse cardiac events (change in =13.8; <0.001). Conclusions Cardiac dysfunction is observed across all muscular dystrophy subtypes; however, the subtypes demonstrate distinct phenotypic profiles. Myocardial deformation analysis highlights unique markers of principal strain that improve risk assessment over other strain markers, LV ejection fraction, and late gadolinium enhancement in this vulnerable patient population.
Topics: Adult; Humans; Female; Male; Prognosis; Contrast Media; Myotonic Dystrophy; Magnetic Resonance Imaging, Cine; Gadolinium; Magnetic Resonance Imaging; Ventricular Function, Left; Stroke Volume; Heart Diseases; Fibrosis; Magnetic Resonance Spectroscopy
PubMed: 37929714
DOI: 10.1161/JAHA.123.030229