RARE DISEASE
Emery-Dreifuss muscular dystrophy
Emery-Dreifuss muscular dystrophy
Emery-Dreifuss muscular dystrophy
Synonyms: EDMD
Synonyms: EDMD
Synonyms: EDMD
Drug discovery
144
papers
On emerging therapies
Overview
Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disorder characterized by early-onset joint contractures (elbows, ankles, neck), progressive humero-peroneal muscle weakness, and life-threatening cardiac conduction defects/arrhythmias. Caused by mutations in EMD (X-linked), LMNA (autosomal), or FHL1 genes, it manifests clinically by age 10, with cardiomyopathy often detectable by age 20. Disease progression varies, with mortality linked to heart failure, arrhythmias, or thromboembolic events.
Burden
Progressive mobility loss (wheelchair dependence in adulthood) [4][11], frequent cardiac device implantation [14], and reduced life expectancy secondary to sudden cardiac death [12].
Chronic care needs (physical therapy, cardiac surveillance) impose significant socioeconomic and psychosocial burdens [12][19].
Therapies
Symptomatic management: Physiotherapy for contractures, pacemakers/ICDs for arrhythmias [1][17], and anticoagulation for atrial fibrillation [14].
Surgical interventions: Tendon release for contractures, spinal stabilization for scoliosis [1][4].
Cardiac monitoring: Annual ECGs/echocardiograms to detect conduction defects or cardiomyopathy [12][17].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
144 drug discovery papers about Emery-Dreifuss muscular dystrophy. Recent publications:
144 drug discovery papers about Emery-Dreifuss muscular dystrophy. Recent publications:
categories:
Small molecules
cell therapies
2026-01-01 | Successful Heart Transplantation in a Woman With LMNA‐Related Emery–Dreifuss Muscular Dystrophy: A Case Report and Literature Review
Introduction Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder frequently associated with progressive cardiac involvement, particularly in patients carrying LMNA mutations. End‐stage heart failure may develop despite optimal medical and device therapy, although heart transplantation remains an uncommon therapeutic option because of concerns regarding the underlying neuromuscular disease. Case Presentation We report the case of a 35‐year‐old woman with LMNA ‐related EDMD who developed advanced biventricular heart failure complicated by recurrent atrial and ventricular arrhythmias, complete atrioventricular block, implantable cardioverter‐defibrillator implantation, and multiple thromboembolic events. Pretransplant neurological and respiratory assessments demonstrated preserved functional status without severe musculoskeletal impairment. Owing to refractory ventricular tachyarrhythmias and progressive heart failure, the patient underwent orthotopic heart transplantation in December 2022. Postoperative recovery was uneventful, with discharge on postoperative day 21. At 43‐month follow‐up, she remained alive with preserved graft function, no episodes of rejection, stable respiratory function, and no evidence of neurological deterioration. Conclusion Heart transplantation may be a feasible treatment option for carefully selected patients with EDMD and end‐stage heart failure. Careful multidisciplinary assessment is essential to identify candidates who can achieve favorable long‐term outcomes.
2024-12-08 | Human iPSCs-derived muscle cells as a new model for investigation of EDMD1 pathogenesis.
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene, which encodes the nuclear envelope protein emerin. Despite understanding the genetic basis of the disease, the molecular mechanism underlying muscle and cardiac pathogenesis remains elusive. Progress is restricted by the limited availability of patient-derived samples, therefore there is an urgent need for human-specific cellular models. In this study, we present the generation and characterization of induced pluripotent stem cell (iPSC) lines derived from EDMD1 patients carrying EMD mutations that lead to truncated or absent emerin, together with iPSCs from healthy donor. The patient-specific iPSCs exhibit stable karyotypes, maintain appropriate morphology, express pluripotency markers and demonstrate the ability to differentiate into three germ layers. To model EDMD1, these iPSCs were differentiated into myogenic progenitors, myoblasts and multinucleated myotubes, which represent all stages of myogenesis. Each developmental stage was validated by the presence of stage-specific markers, ensuring the accuracy of the model. We present the first iPSC-based in vitro platform that captures the complexity of EDMD1 pathogenesis during myogenesis. This model can significantly contribute to understanding disease mechanisms and develop the targeted therapeutic strategies for EDMD1.
2022-12-27 | Cardiac manifestations and clinical management of X-linked Emery-Dreifuss muscular dystrophy: a case series
Heart disease is an under-recognized cause of morbidity and mortality in patients with Emery-Dreifuss muscular dystrophy (EDMD). Arrhythmias and conduction delays are highly prevalent and given the rarity of this disease the patient care process remains poorly defined.This study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive EDMD. Patients were assessed and managed on a case-by-case basis. Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations (12-lead electrocardiogram, 24 hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers). Conduction disease, requiring permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period five years the cardiac status was shown to have stabilized in all these patients.We demonstrate the presentation of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with X-linked EDMD. Cardiac medications and pacemaker therapy are shown to prevent adverse outcomes from these complications. Patients with EDMD are expected to develop heart disease early and prior to the development of an overt neuromuscular phenotype. These patients should be closely monitored in a multidisciplinary setting for effective management to improve their clinical outcomes.
2021-08-01 | Generation of one control and four iPSCs clones from patients with Emery-Dreifuss muscular dystrophy type 1
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene coding for a nuclear envelope protein emerin. We generated and characterized induced pluripotent stem cells (iPSCs) from two EDMD1 patients bearing a mutation c.del153C and from one healthy donor. That mutation leads to generation of premature STOP codon. Established iPSCs are very valuable tool for disease pathogenesis investigation and for the development of new therapeutic methods after differentiation to cardiac or muscle cells. Obtained iPSCs show the proper morphology, pluripotency markers expression, normal karyotype and potential to differentiate into three germ layers.
2016-12-01 | Dilated cardiomyopathy with severe arrhythmias in Emery-Dreifuss muscular dystrophy: from ablation to heart transplantation.
We present 38-years male patient. He has suffered from muscle weakness since 5 years. Arrhythmias appeared at the age of 32. In 37 years he had sick sinus syndrome, transient AV block II degree, paroxysmal atrial fibrillation, atrial flutter, ventricular arrhythmias. At this time, dilated cardiomyopathy was also detected. The evaluation revealed knees and elbows contractures, increased level of creatine kinase. The genetic testing revealed a frame shift deletion c.del619C in the emerin (EMD) gene and c.IVS4-13T> A in the lamin (LMNA) gene, and c.del619C deletion in the heterozygous state in a patient`s mother. Radiofrequency ablation of cavotricuspid isthmus, implantable cardioverter-defibrillator (ICD) implantation were performed. Heart transplantation was performed nine months later, due to severe heart failure and electrical storm. A morphological evaluation revealed sclerosis, atrophy and hypertrophy of cardiomyocytes. He underwent an induction therapy with (basiliximab) methylprednisolone, tacrolimus, mycophenolate after heart transplantation. During 40 months after transplantation, patient`s condition is satisfactory.heart failure in Emery-Dreifuss muscular dystrophy can progress quickly unless the previously stable condition. The use of correct regimens of immunosuppression therapy provides good long-term results of the heart transplantation.
gene therapies
2026-09-14 | Assessment of emerin gene transfer in models of X-linked Emery-Dreifuss muscular dystrophy
X-linked Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin, a 254-amino acid integral protein of the inner nuclear membrane. Given that almost all EMD mutations lead to loss of protein expression, we hypothesized that emerin replacement gene therapy could be an effective strategy to treat X-linked EDMD. We designed a serotype rh74 adeno-associated virus vector containing a tMCK promoter linked to a codon-optimized human emerin cDNA (AAV-tMCK-hEMD) to drive emerin expression in striated muscle. We administered this vector to Emd −/y mice and examined emerin expression and assessed various safety parameters. We also examined emerin expression in EMD −/y induced pluripotent stem cell-derived cardiomyocytes. Treatment with AAV-tMCK-hEMD produced robust expression of human emerin in heart and skeletal muscle of Emd −/y mice as demonstrated by immunoblotting and immunofluorescence microscopy. Systemic administration of AAV-tMCK-hEMD to Emd −/y mice did not lead to significant alterations in serum biochemistries, heart, skeletal muscle or liver histology, or major gene expression changes in the heart. Transduction of EMD −/y induced pluripotent stem cell-derived cardiomyocytes with AAV-tMCK-hEMD resulted in emerin expression, demonstrating its utility in a human striated muscle cell model system. These results showing effective adeno-associated virus vector-mediated expression of emerin in striated muscle in preclinical models provide proof of concept for potential emerin gene therapy in patients with X-linked EDMD.
2026-05-13 | Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells.
During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.
2026-03-27 | Cardiac Involvement in Emery-Dreifuss Muscular Dystrophy: From Arrhythmias to Heart Failure and Sudden Death: A Contemporary Review
Background: Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder within the spectrum of nuclear envelope diseases, classically characterized by early musculo-tendinous contractures, slowly progressive myopathy and cardiac involvement dominated by conduction disease and arrhythmias, with variable evolution toward cardiomyopathy and heart failure. Methods: We performed a narrative synthesis of the contemporary literature, focusing on clinically relevant and high-impact evidence. Particular attention was given to diagnostic strategies, risk stratification, and therapeutic approaches applicable in real-world clinical settings. Results: Cardiac involvement in EDMD encompasses a broad spectrum, including atrial disease and conduction disturbances, ventricular arrhythmias, dilated cardiomyopathy, thromboembolic complications, and sudden cardiac death. The heterogeneity of phenotypic expression reflects underlying genetic diversity. Early recognition and systematic cardiovascular surveillance are essential to guide timely intervention, including device therapy and heart failure management. Despite growing awareness, significant gaps remain in risk prediction and standardized management pathways. Conclusions: EDMD represents a paradigmatic model of cardiomyopathy with prominent electrical instability and systemic implications. A structured, genotype- and phenotype-aware strategy, centered on early surveillance, targeted rhythm and thromboembolic risk management, and timely device therapy, can improve clinical decision-making in real-world settings. Future perspectives include the integration of precision medicine and the development of gene-targeted therapies, with the potential to shift from symptomatic management toward disease-modifying strategies. This narrative review aims to provide an updated and comprehensive, clinically actionable narrative synthesis of cardiovascular manifestations across EDMD genotypes and phenotypes, integrating rare and under-recognized high-impact presentations, and to outline pragmatic diagnostic and therapeutic pathways for real-world care while highlighting unmet needs and future directions.
2025-10-28 | Emery Dreifuss muscular dystrophy masquerading as limb girdle muscular dystrophy type 2 due to a novel mutation in emerin gene
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2025-09-13 | Profibrotic Molecules Are Reduced in CRISPR-Edited Emery-Dreifuss Muscular Dystrophy Fibroblasts.
Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD, LMNA, SYNE1, SYNE2, and other related genes. The disease is characterized by joint contractures, muscle weakening and wasting, and heart conduction defects associated with dilated cardiomyopathy. Previous studies demonstrated the activation of fibrogenic molecules such as TGFbeta 2 and CTGF in preclinical models of EDMD2 and increased secretion of TGFbeta 2 in patient serum. A wide screening of patient cells suggested fibrosis, metabolism, and myogenic signaling as the most affected pathways in various EDMD forms. In this study, we show that alpha-smooth muscle actin-positive myofibroblasts are overrepresented in patient fibroblast cultures carrying EMD, LMNA, or SYNE2 mutations, and profibrotic miRNA-21 is upregulated. Upon CRISPR/Cas correction of the mutated EMD or LMNA sequence in EDMD1 or EDMD2 fibroblasts, respectively, we observe a reduced expression of fibrogenic molecules. However, in patient myoblasts, neither fibrogenic proteins nor miRNA-21 were upregulated; instead, miRNA-21-5p was downregulated along with muscle-specific miRNA-133b and miRNA-206, which have a crucial role in muscle cell homeostasis. These observations suggest that the conversion of laminopathic fibroblasts into a profibrotic phenotype is a determinant of EDMD-associated muscle fibrosis, while miRNA-206-dependent defects of laminopathic myoblasts, including altered regulation of VEGF levels, contribute to muscle cell deterioration. Notably, our study provides a proof-of-principle for the application of gene correction to EDMD1 and EDMD2 and presents EDMD1 isogenic cells that exhibit an almost complete rescue of a disease-specific miRNA signature. These cells can be used as experimental models for studying muscular laminopathies.
small molecules
2026-08-26 | Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defective nuclear mechanics and transcriptional regulation, yet these mechanisms cannot explain how lamina defects propagate across the cell to produce the complex pathology of laminopathies. Here, we reveal an emerging pathway linking nuclear lamina dysfunction to cytoplasmic reorganization. Using Caenorhabditis elegans EDMD models, we show that disease-linked lamin variants reduce cytoplasmic mesoscale crowding, increase molecular diffusivity, and disrupt nuclear positioning and endoplasmic reticulum architecture, which mirror phenotypes caused by ribosome depletion. Lamin dysfunction also lowers nucleolar fibrillarin levels and ribosome abundance, revealing a nucleolar-ribosomal axis that transmits nuclear defects to the cytoplasm. Loss of the redundant LEM-domain proteins emr-1 and lem-2 phenocopied lamin mutants, indicating that cytoplasmic disorganization is a shared hallmark of EDMD. These findings connect nuclear architecture to whole-cell biophysics and suggest therapeutic strategies aimed at restoring ribosome function.
2026-07-28 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-10-03 | Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis controlling cytoplasmic macromolecular crowding.
Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defects in nuclear mechanics and transcription regulation. Yet these models do not fully explain the complexity of EDMD or other laminopathies. Here, we uncover an emerging pathway linking nuclear lamina defects to the reorganization of cytoplasmic biophysics, revealing how nuclear dysfunction cascades throughout the cell. Using Caenorhabditis elegans EDMD models, we demonstrate that lamin mutations dramatically alter cytoplasmic organization, reducing macromolecular crowding and increasing diffusivity of 40 nm Genetically Encoded Multimeric (GEM) nanoparticles. These striking biophysical changes coincide with nuclear positioning defects and collapsed endoplasmic reticulum architecture, mirroring phenotypes associated with ribosome depletion. We propose a mechanism where mutations in the C. elegans lamin lmn-1 disrupt nucleolar density and ribosome biogenesis, creating a nucleolar-ribosomal axis that propagates defects from the nucleus to the cytoplasm. Genetic interactions between lmn-1 and ribosomes support this regulatory relationship. While individual depletion of other nuclear envelope proteins produces minimal effects, combined loss of the functionally redundant emerin ortholog emr-1 and LEM-domain protein lem-2 phenocopied lmn-1 mutants, demonstrating that cytoplasmic biophysical disruption lies at EDMD's pathogenic core. Our findings establish a paradigm where nuclear lamina defects fundamentally rewire cellular biophysics through nucleolar-ribosomal dysfunction, opening transformative therapeutic avenues for treating laminopathies.
2025-04-27 | iPSC-derived cardiomyocytes and engineered heart tissues reveal suppressed JAK2/STAT3 signaling in LMNA-related emery-dreifuss muscular dystrophy.
LMNA mutation related Emery-Dreifuss muscular dystrophy (LMNA-related EDMD), is a rare genetic disorder often involving life-threatening cardiac complications. However, the molecular links between LMNA mutations and their related EDMD cardiac phenotypes have remained unclear. Here, using EDMD patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we link the LMNA L204P mutation with the pathogenic phenotypes of arrhythmia and contractile dysfunction. Using multi-omics analysis, we then show that LMNA L204P results in decreased chromatin accessibility, leading to the downregulation of JAK2 in EDMD iPSC-CMs. Mechanistically, JAK2/STAT3 signaling pathway suppression in EDMD iPSC-CMs is shown to cause mitochondrial dysfunction and oxidative stress, ultimately resulting in the above phenotypes. Conversely, pharmacological or genetic activation of JAK2/STAT3 signaling effectively rescues both the arrhythmic and contractile dysfunction phenotypes in EDMD iPSC-CMs via improvements in mitochondrial function. In addition, whilst EDMD engineered heart tissues (EHTs) display dysfunctional contractile force generation, this can also be significantly alleviated by STAT3 activation. Taken together, we present chromatin compartment change-mediated JAK2/STAT3 suppression as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating the JAK2/STAT3 signaling pathway may hold the potential to serve as a novel therapeutic strategy for this condition.
proteins
2026-04-17 | WNT5a-Mediated Aberrant Actin Filament Dynamics Drive Cardiac Pathogenic Phenotypes in LMNA-Related Emery-Dreifuss Muscular Dystrophy.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disorder characterized by early-onset joint contractures, progressive muscle atrophy, and cardiac abnormalities. Patients with EDMD carrying LMNA sequence variations often exhibit severe cardiac manifestations, including frequent atrioventricular block and ventricular tachycardia. Approximately 20% of those patients may ultimately require heart transplantation. The molecular mechanisms by which LMNA sequence variations lead to EDMD remain unknown. Five clinically diagnosed patients with EDMD carrying LMNA sequence variations were recruited. Patient-specific induced pluripotent stem cells (iPSCs) were generated using a nonintegrating Sendai virus. Previously generated iPSCs, derived from 2 healthy donors, were used as controls. The LMNA L204P sequence variation was corrected by genome editing in EDMD iPSC lines to generate isogenic controls. All iPSC-derived cardiomyocytes (iPSC-CMs) were generated using a monolayer-based differentiation protocol. Three-dimensional, strip-format, and force-generating human engineered heart tissues were generated from iPSC-CMs. A knock-in mouse model carrying the Lmna L204P sequence variation was also generated. EDMD-specific iPSC-CMs exhibited a variety of deleterious phenotypes, including disorganized sarcomeres, abnormal nuclear envelope structure, arrhythmias, and contractile dysfunction, when compared with control and gene-corrected iPSC-CMs. Multi-omics analysis further revealed that LMNA directly binds the WNT5A promoter and the Leu204Pro sequence variation reduces chromatin accessibility and WNT5A transcription in EDMD iPSC-CMs. WNT5a (Wnt family member 5a)/RhoA (Ras homolog family member A) signaling inactivation was shown to lead to actin depolymerization and inhibition of actin polymerization in EDMD iPSC-CMs. This results in a deformed nuclear envelope, contractile dysfunction, and impaired trafficking of Cx43 (connexin 43). The impairment of Cx43 trafficking causes reduced distribution of Cx43 at cell-cell borders, contributing to the arrhythmic phenotype in EDMD iPSC-CMs. Pharmacological interventions of exogenous WNT5a supplementation, RhoA activator, or an actin polymerization stabilizer effectively rescued the pathogenic phenotypes of EDMD iPSC-CMs. EDMD engineered heart tissues displayed dysfunctional contractile force generation, which was significantly alleviated by RhoA activator. Lmna L204P heterozygous knock-in mice exhibited impaired cardiac function and developed cardiac arrhythmias in response to sympathetic stress. We present WNT5a-mediated aberrant actin filament dynamics as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating WNT5a/RhoA and stabilizing actin assembly may serve as novel therapeutic strategies for this condition.
2025-06-06 | Cargo recognition of Nesprin-2 by the dynein adapter Bicaudal D2 for a nuclear positioning pathway that is important for neuronal migration.
Nesprin-2 is a subunit of LINC complexes, which span the nuclear envelope and have key roles in mechanotransduction and nuclear positioning during brain and muscle development. Nesprin-2 interacts with the plus-end directed motor kinesin-1 and the dynein adapter Bicaudal D2 (BicD2), which in turn recruits the minus-end directed motor cytoplasmic dynein to position the nucleus during neuronal migration of postmitotic neurons, but the molecular details of these interactions are elusive. Here we present a structural model of a minimal Nesprin-2/BicD2 complex. A structure prediction with a PAE score in the high confidence range was obtained from AlphaFold and experimentally validated by mutagenesis, binding assays and biophysical studies. The core of the binding site is formed by spectrin repeats of Nesprin-2, which form an alpha-helical bundle with the cargo-binding domain of BicD2. The minimal Nesprin-2 fragment also interacts robustly with full-length BicD2. The BicD2-binding site is separated by a ∼65 residue intrinsically disordered linker from the LEWD sequence motif, that acts as kinesin-1 recruitment site, and we propose that both kinesin-1 and BicD2/dynein interact with Nesprin-2 simultaneously. We propose that structurally distinct interactions between BicD2 and its cargo adapters Nesprin-2, Nup358 and Rab6, as well as distinctions in the adjacent kinesin-1 recruiting sites could finetune overall motility for these transport pathways that have important roles in brain and muscle development. Mutations of Nesprin-2 and BicD2 cause devastating brain and muscle developmental diseases, including Emery-Dreifuss Muscular Dystrophy and spinal muscular atrophy, and results may help devise therapies for these diseases.
2023-10-23 | Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty
Clinical frailty affects ∼10% of people over age 65 and is studied in a chronically inflamed (Interleukin-10 knockout; “IL10-KO”) mouse model. Frailty phenotypes overlap the spectrum of diseases (“laminopathies”) caused by mutations in LMNA . LMNA encodes nuclear intermediate filament proteins lamin A and lamin C (“lamin A/C”), important for tissue-specific signaling, metabolism and chromatin regulation. We hypothesized that wildtype lamin A/C associations with tissue-specific partners are perturbed by chronic inflammation, potentially contributing to dysfunction in frailty. To test this idea we immunoprecipitated native lamin A/C and associated proteins from skeletal muscle, hearts and brains of old (21–22 months) IL10-KO versus control C57Bl/6 female mice, and labeled with Tandem Mass Tags for identification and quantitation by mass spectrometry. We identified 502 candidate lamin-binding proteins from skeletal muscle, and 340 from heart, including 62 proteins identified in both tissues. Candidates included frailty phenotype-relevant proteins Perm1 and Fam210a, and nuclear membrane protein Tmem38a, required for muscle-specific genome organization. These and most other candidates were unaffected by IL10-KO, but still important as potential lamin A/C-binding proteins in native heart or muscle. A subset of candidates (21 in skeletal muscle, 30 in heart) showed significantly different lamin A/C-association in an IL10-KO tissue ( p < 0.05), including AldoA and Gins3 affected in heart, and Lmcd1 and Fabp4 affected in skeletal muscle. To screen for binding, eleven candidates plus prelamin A and emerin controls were arrayed as synthetic 20-mer peptides (7-residue stagger) and incubated with recombinant purified lamin A “tail” residues 385–646 under relatively stringent conditions. We detected strong lamin A binding to peptides solvent exposed in Lmcd1, AldoA, Perm1, and Tmem38a, and plausible binding to Csrp3 (muscle LIM protein). These results validated both proteomes as sources for native lamin A/C-binding proteins in heart and muscle, identified four candidate genes for Emery-Dreifuss muscular dystrophy (CSRP3, LMCD1, ALDOA, and PERM1), support a lamin A-interactive molecular role for Tmem38A, and supported the hypothesis that lamin A/C interactions with at least two partners (AldoA in heart, transcription factor Lmcd1 in muscle) are altered in the IL10-KO model of frailty.
2015-11-02 | Nesprin-2 mediated nuclear trafficking and its clinical implications
Nuclear translocation of proteins has a crucial role in the pathogenesis of cancer, Alzheimer disease and viral infections. A complete understanding of nuclear trafficking mechanisms is therefore necessary in order to establish effective intervention strategies. Here we elucidate the role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear transport. Nesprin-2 is an actin-binding nuclear envelope (NE) protein with roles in maintaining nuclear structure and location, regulation of transcription and mechanotransduction. Upon depletion of Nesprin-2 using shRNA, HaCaT cells show abnormal localization of the shuttling proteins BRCA1 and NF-κB. We show that their nuclear transport is unlikely due to the canonical RAN mediated nuclear import, but rather to a RAN independent Ca2+/Calmodulin driven mechanism involving Nesprin-2. We report novel interactions between the actin-binding domain of Nesprin-2 and Calmodulin and between the NLS containing region of BRCA1 and Calmodulin. Strikingly, displacing Nesprins from the NE resulted in increased steady state Ca2+ concentrations in the cytoplasm suggesting a previously unidentified role of Nesprins in Ca2+ regulation. On comparing Nesprin-2 and BRCA1 localization in the ovarian cancer cell lines SKOV-3 and Caov-3, Nesprin-2 and BRCA1 were localized to the NE envelope and the nucleus in SKOV-3, respectively, and to the cytoplasm in Caov-3 cells. Fibroblasts obtained from EDMD5 (Emery Dreifuss muscular dystrophy) patients showed loss of Nesprin-2 from the nuclear envelope, corresponding reduced nuclear localization of BRCA1 and enhanced cytoplasmic Ca2+. Taken together, the data suggests a novel role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear trafficking and provides new insights which can guide future therapies.
2014-12-16 | Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells
During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin-1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-type-specific nuclear positioning during development.
other
2026-02-01 | Disruption of Nuclear‐Cytoskeletal Linkage by Coil‐1a LMNA Mutations in Emery–Dreifuss Muscular Dystrophy
ABSTRACT Background Emery–Dreifuss muscular dystrophy (EDMD) is a progressive genetic myopathy that mainly affects the muscles used for movement (skeletal muscles) and the heart (cardiac muscles). The disease is frequently associated with mutations in genes encoding nuclear envelope proteins, most notably LMNA, which encodes lamin A—a critical structural component of the nuclear lamina. Lamin A plays a pivotal role in maintaining nuclear architecture and mechanotransduction. In contrast to most other cell types, nuclei in healthy skeletal muscle fibres are typically localized at the periphery of the myofiber. However, muscle biopsies from EDMD patients often reveal aberrant nuclear morphology and ectopic nuclear positioning, with nuclei clustered or mislocalized toward the centre of the myofiber. Despite these characteristic nuclear abnormalities, the molecular mechanisms underlying nuclear mispositioning in EDMD remain incompletely understood. In particular, the interaction networks between EDMD‐related mutant lamin A and other nuclear and cytoskeletal components that govern nuclear positioning are poorly characterized in the current literature. Methods EDMD‐related lamin A variants (L35V, L38F or Y45C), which are located within the Coil‐1a domain, were overexpressed in RD cells. Mesenchymal stem cells (MSCs) were generated by redifferentiating induced pluripotent stem cells (iPSCs), which were derived from fibroblasts of an EDMD (L35P) patient. To investigate morphological and molecular abnormalities caused by mutations, immunofluorescence imaging, immunoblotting and subcellular fractionation were performed. Functional consequences of these morphological alterations were evaluated by assessing mechanotransduction signalling and cell viability. Results EDMD‐related LMNA mutations (L35V, L38F, Y45C) in the Coil‐1a domain induced multilobular nuclear morphology, accompanied by a decrease in nuclear contour ratio (1.9–3.0‐fold vs. WT, p < 0.0001). Similarly, patient‐derived MSCs (L35P‐MSCs) exhibited a ~2.28‐fold decrease in contour ratio relative to healthy subject‐derived MSCs. Abnormal nuclear shape was associated with structural alterations in nuclear‐cytoskeletal proteins and nuclear positioning regulators. Mechanosensing activity, assessed by YAP1 nuclear translocation, was increased (~1.72‐fold vs. Nor‐CTRL, p < 0.01), and nuclear fragility under physical stress was elevated by ~20% (vs. Nor‐CTRL, p < 0.0001). Treatment with mutation‐specific ASOs in patient‐derived MSCs restored the contour ratio (~1.97‐fold vs. NC‐CTRL, p < 0.01), normalized nuclear‐cytoskeletal organization, reduced mechanosensing response (~1.65‐fold vs. NC‐CTRL, p < 0.01) and decreased nuclear fragility by ~11% (vs. NC‐CTRL, p < 0.0001). Conclusions Our findings indicate that nuclear morphological alterations contribute to the impaired nuclear‐cytoskeletal integrity and nuclear positioning, which are closely linked to cellular mechanics and function. Mutation‐specific ASO treatment alleviated these nuclear defects, suggesting that ASO‐based therapeutic strategies may provide a mutation‐targeted approach to correcting nuclear abnormalities in EDMD.
2025-07-08 | Anti-myogenic and profibrotic effect of serum from patients affected by muscular laminopathies.
Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2) and LMNA-related congenital muscular dystrophy (L-CMD) are caused by mutations in LMNA gene. Both pathologies are characterized by joint contractures, muscle weakness and wasting and cardiac involvement. In the last few years, circulating factors have been proposed to play a critical role in the pathogenesis of these diseases. Based on this consideration, we studied the effect of laminopathic serum on the myogenic differentiation in healthy human myoblasts in culture. We observed impaired myogenesis and increased fibrosis in myoblast cultures conditioned with laminopathic serum and a dramatic increase in the level of profibrotic and proinflammatory cytokines in the cell culture supernatants. These results strongly support the pathogenic role of circulating factors in muscular laminopathies and pave the way to a possible therapeutic strategy.
2025-06-11 | Development of Emerin mRNA Lipid Nanoparticles to Rescue Myogenic Differentiation
Abstract Emery-Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD . Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms, without addressing the underlying cause – lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs have been studied for decades and have recently been used clinically for vaccination and treatment of myriad of diseases. Here, we show treatment of emerin-null myogenic progenitors with LNPs encapsulating emerin mRNA causes robust emerin protein expression that persists for at least 4 days. Treatment of differentiating emerin-null myogenic progenitors with 2.5 pg/cell emerin LNPs significantly improved their differentiation. Toxicity profiling of emerin mRNA LNP (EMD-LNP) dosing shows little toxicity at the effective dose. These data support the potential use of EMD-LNPs as a viable treatment option and establishes its utility for studying EDMD pathology.
2020-05-05 | Emery-Dreifuss muscular dystrophy: focal point nuclear envelope.
Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin and LMNA encoding A-type lamins, proteins of the nuclear envelope. In the past decade, there has been an extraordinary burst of research on the nuclear envelope. Discoveries resulting from this basic research have implications for better understanding the pathogenesis and developing treatments for EDMD. Recent clinical research has confirmed that EDMD is one of several overlapping skeletal muscle phenotypes that can result from mutations in EMD and LMNA with dilated cardiomyopathy as a common feature. Basic research on the nuclear envelope has provided new insights into how A-type lamins and emerin function in force transmission throughout the cell, which may be particularly important in striated muscle. Much of the recent research has focused on the heart and LMNA mutations. Prevalence and outcome studies have confirmed the relative severity of cardiac disease. Robust mouse models of EDMD caused by LMNA mutations has allowed for further insight into pathogenic mechanisms and potentially beneficial therapeutic approaches. Recent clinical and basic research on EDMD is gradually being translated to clinical practice and possibly novel therapies.
2019-09-01 | Pathogenic Abnormal Splicing Due to Intronic Deletions that Induce Biophysical Space Constraint for Spliceosome Assembly
A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5′ splice-site (5′SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5′SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5′SS-branchpoint length in our index EMD case subject defines 45–47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5′SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics. A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5′ splice-site (5′SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5′SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5′SS-branchpoint length in our index EMD case subject defines 45–47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5′SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.
cell therapies
2026-01-01 | Successful Heart Transplantation in a Woman With LMNA‐Related Emery–Dreifuss Muscular Dystrophy: A Case Report and Literature Review
Introduction Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder frequently associated with progressive cardiac involvement, particularly in patients carrying LMNA mutations. End‐stage heart failure may develop despite optimal medical and device therapy, although heart transplantation remains an uncommon therapeutic option because of concerns regarding the underlying neuromuscular disease. Case Presentation We report the case of a 35‐year‐old woman with LMNA ‐related EDMD who developed advanced biventricular heart failure complicated by recurrent atrial and ventricular arrhythmias, complete atrioventricular block, implantable cardioverter‐defibrillator implantation, and multiple thromboembolic events. Pretransplant neurological and respiratory assessments demonstrated preserved functional status without severe musculoskeletal impairment. Owing to refractory ventricular tachyarrhythmias and progressive heart failure, the patient underwent orthotopic heart transplantation in December 2022. Postoperative recovery was uneventful, with discharge on postoperative day 21. At 43‐month follow‐up, she remained alive with preserved graft function, no episodes of rejection, stable respiratory function, and no evidence of neurological deterioration. Conclusion Heart transplantation may be a feasible treatment option for carefully selected patients with EDMD and end‐stage heart failure. Careful multidisciplinary assessment is essential to identify candidates who can achieve favorable long‐term outcomes.
2024-12-08 | Human iPSCs-derived muscle cells as a new model for investigation of EDMD1 pathogenesis.
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene, which encodes the nuclear envelope protein emerin. Despite understanding the genetic basis of the disease, the molecular mechanism underlying muscle and cardiac pathogenesis remains elusive. Progress is restricted by the limited availability of patient-derived samples, therefore there is an urgent need for human-specific cellular models. In this study, we present the generation and characterization of induced pluripotent stem cell (iPSC) lines derived from EDMD1 patients carrying EMD mutations that lead to truncated or absent emerin, together with iPSCs from healthy donor. The patient-specific iPSCs exhibit stable karyotypes, maintain appropriate morphology, express pluripotency markers and demonstrate the ability to differentiate into three germ layers. To model EDMD1, these iPSCs were differentiated into myogenic progenitors, myoblasts and multinucleated myotubes, which represent all stages of myogenesis. Each developmental stage was validated by the presence of stage-specific markers, ensuring the accuracy of the model. We present the first iPSC-based in vitro platform that captures the complexity of EDMD1 pathogenesis during myogenesis. This model can significantly contribute to understanding disease mechanisms and develop the targeted therapeutic strategies for EDMD1.
2022-12-27 | Cardiac manifestations and clinical management of X-linked Emery-Dreifuss muscular dystrophy: a case series
Heart disease is an under-recognized cause of morbidity and mortality in patients with Emery-Dreifuss muscular dystrophy (EDMD). Arrhythmias and conduction delays are highly prevalent and given the rarity of this disease the patient care process remains poorly defined.This study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive EDMD. Patients were assessed and managed on a case-by-case basis. Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations (12-lead electrocardiogram, 24 hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers). Conduction disease, requiring permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period five years the cardiac status was shown to have stabilized in all these patients.We demonstrate the presentation of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with X-linked EDMD. Cardiac medications and pacemaker therapy are shown to prevent adverse outcomes from these complications. Patients with EDMD are expected to develop heart disease early and prior to the development of an overt neuromuscular phenotype. These patients should be closely monitored in a multidisciplinary setting for effective management to improve their clinical outcomes.
2021-08-01 | Generation of one control and four iPSCs clones from patients with Emery-Dreifuss muscular dystrophy type 1
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a rare genetic disease caused by mutations in the EMD gene coding for a nuclear envelope protein emerin. We generated and characterized induced pluripotent stem cells (iPSCs) from two EDMD1 patients bearing a mutation c.del153C and from one healthy donor. That mutation leads to generation of premature STOP codon. Established iPSCs are very valuable tool for disease pathogenesis investigation and for the development of new therapeutic methods after differentiation to cardiac or muscle cells. Obtained iPSCs show the proper morphology, pluripotency markers expression, normal karyotype and potential to differentiate into three germ layers.
2016-12-01 | Dilated cardiomyopathy with severe arrhythmias in Emery-Dreifuss muscular dystrophy: from ablation to heart transplantation.
We present 38-years male patient. He has suffered from muscle weakness since 5 years. Arrhythmias appeared at the age of 32. In 37 years he had sick sinus syndrome, transient AV block II degree, paroxysmal atrial fibrillation, atrial flutter, ventricular arrhythmias. At this time, dilated cardiomyopathy was also detected. The evaluation revealed knees and elbows contractures, increased level of creatine kinase. The genetic testing revealed a frame shift deletion c.del619C in the emerin (EMD) gene and c.IVS4-13T> A in the lamin (LMNA) gene, and c.del619C deletion in the heterozygous state in a patient`s mother. Radiofrequency ablation of cavotricuspid isthmus, implantable cardioverter-defibrillator (ICD) implantation were performed. Heart transplantation was performed nine months later, due to severe heart failure and electrical storm. A morphological evaluation revealed sclerosis, atrophy and hypertrophy of cardiomyocytes. He underwent an induction therapy with (basiliximab) methylprednisolone, tacrolimus, mycophenolate after heart transplantation. During 40 months after transplantation, patient`s condition is satisfactory.heart failure in Emery-Dreifuss muscular dystrophy can progress quickly unless the previously stable condition. The use of correct regimens of immunosuppression therapy provides good long-term results of the heart transplantation.
gene therapies
2026-09-14 | Assessment of emerin gene transfer in models of X-linked Emery-Dreifuss muscular dystrophy
X-linked Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin, a 254-amino acid integral protein of the inner nuclear membrane. Given that almost all EMD mutations lead to loss of protein expression, we hypothesized that emerin replacement gene therapy could be an effective strategy to treat X-linked EDMD. We designed a serotype rh74 adeno-associated virus vector containing a tMCK promoter linked to a codon-optimized human emerin cDNA (AAV-tMCK-hEMD) to drive emerin expression in striated muscle. We administered this vector to Emd −/y mice and examined emerin expression and assessed various safety parameters. We also examined emerin expression in EMD −/y induced pluripotent stem cell-derived cardiomyocytes. Treatment with AAV-tMCK-hEMD produced robust expression of human emerin in heart and skeletal muscle of Emd −/y mice as demonstrated by immunoblotting and immunofluorescence microscopy. Systemic administration of AAV-tMCK-hEMD to Emd −/y mice did not lead to significant alterations in serum biochemistries, heart, skeletal muscle or liver histology, or major gene expression changes in the heart. Transduction of EMD −/y induced pluripotent stem cell-derived cardiomyocytes with AAV-tMCK-hEMD resulted in emerin expression, demonstrating its utility in a human striated muscle cell model system. These results showing effective adeno-associated virus vector-mediated expression of emerin in striated muscle in preclinical models provide proof of concept for potential emerin gene therapy in patients with X-linked EDMD.
2026-05-13 | Emerin is necessary for microtubule-organizing center translocation to the nuclear envelope of muscle cells.
During myogenic differentiation, the Microtubule-Organizing Center (MTOC) is relocated to the nuclear envelope by a molecular platform including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins, A Kinase Anchoring Proteins (AKAP9 and AKAP6) and Pericentriolar Material 1 (PCM-1). Here, we show that emerin is required for centrosomal protein recruitment to the nuclear periphery of myonuclei and microtubule dynamics. In fact, in type 1 Emery-Dreifuss Muscular Dystrophy (EDMD1), loss of emerin was associated with altered pericentrin recruitment to the nuclear envelope, LINC protein impairment at the nuclear poles of myonuclei and microtubule organization defects. As a consequence, dynein, mitochondrial distribution and nuclear alignment along the longitudinal axis of the myotubes were altered in EDMD1 myotubes. Moreover, reduced levels of AKAP6 and PKA were detected at the nuclear periphery of EDMD1 myotubes, possibly contributing to an aberrant nuclear localization of the mechanosensing factor YAP. Upon rescue of emerin expression by CRISPR correction of mutated EMD gene: SUN1/2, pericentrin, AKAP6 and PKA were restored at the nuclear envelope and a correct YAP localization was observed in EDMD1 muscle cells. These results show that emerin is required for Nuclear Envelope-MTOC (NE-MTOC) organization in differentiating skeletal muscle cells and suggest that disruption of such complex is a key pathogenetic event in Emery-Dreifuss Muscular Dystrophy.
2026-03-27 | Cardiac Involvement in Emery-Dreifuss Muscular Dystrophy: From Arrhythmias to Heart Failure and Sudden Death: A Contemporary Review
Background: Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder within the spectrum of nuclear envelope diseases, classically characterized by early musculo-tendinous contractures, slowly progressive myopathy and cardiac involvement dominated by conduction disease and arrhythmias, with variable evolution toward cardiomyopathy and heart failure. Methods: We performed a narrative synthesis of the contemporary literature, focusing on clinically relevant and high-impact evidence. Particular attention was given to diagnostic strategies, risk stratification, and therapeutic approaches applicable in real-world clinical settings. Results: Cardiac involvement in EDMD encompasses a broad spectrum, including atrial disease and conduction disturbances, ventricular arrhythmias, dilated cardiomyopathy, thromboembolic complications, and sudden cardiac death. The heterogeneity of phenotypic expression reflects underlying genetic diversity. Early recognition and systematic cardiovascular surveillance are essential to guide timely intervention, including device therapy and heart failure management. Despite growing awareness, significant gaps remain in risk prediction and standardized management pathways. Conclusions: EDMD represents a paradigmatic model of cardiomyopathy with prominent electrical instability and systemic implications. A structured, genotype- and phenotype-aware strategy, centered on early surveillance, targeted rhythm and thromboembolic risk management, and timely device therapy, can improve clinical decision-making in real-world settings. Future perspectives include the integration of precision medicine and the development of gene-targeted therapies, with the potential to shift from symptomatic management toward disease-modifying strategies. This narrative review aims to provide an updated and comprehensive, clinically actionable narrative synthesis of cardiovascular manifestations across EDMD genotypes and phenotypes, integrating rare and under-recognized high-impact presentations, and to outline pragmatic diagnostic and therapeutic pathways for real-world care while highlighting unmet needs and future directions.
2025-10-28 | Emery Dreifuss muscular dystrophy masquerading as limb girdle muscular dystrophy type 2 due to a novel mutation in emerin gene
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2025-09-13 | Profibrotic Molecules Are Reduced in CRISPR-Edited Emery-Dreifuss Muscular Dystrophy Fibroblasts.
Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD, LMNA, SYNE1, SYNE2, and other related genes. The disease is characterized by joint contractures, muscle weakening and wasting, and heart conduction defects associated with dilated cardiomyopathy. Previous studies demonstrated the activation of fibrogenic molecules such as TGFbeta 2 and CTGF in preclinical models of EDMD2 and increased secretion of TGFbeta 2 in patient serum. A wide screening of patient cells suggested fibrosis, metabolism, and myogenic signaling as the most affected pathways in various EDMD forms. In this study, we show that alpha-smooth muscle actin-positive myofibroblasts are overrepresented in patient fibroblast cultures carrying EMD, LMNA, or SYNE2 mutations, and profibrotic miRNA-21 is upregulated. Upon CRISPR/Cas correction of the mutated EMD or LMNA sequence in EDMD1 or EDMD2 fibroblasts, respectively, we observe a reduced expression of fibrogenic molecules. However, in patient myoblasts, neither fibrogenic proteins nor miRNA-21 were upregulated; instead, miRNA-21-5p was downregulated along with muscle-specific miRNA-133b and miRNA-206, which have a crucial role in muscle cell homeostasis. These observations suggest that the conversion of laminopathic fibroblasts into a profibrotic phenotype is a determinant of EDMD-associated muscle fibrosis, while miRNA-206-dependent defects of laminopathic myoblasts, including altered regulation of VEGF levels, contribute to muscle cell deterioration. Notably, our study provides a proof-of-principle for the application of gene correction to EDMD1 and EDMD2 and presents EDMD1 isogenic cells that exhibit an almost complete rescue of a disease-specific miRNA signature. These cells can be used as experimental models for studying muscular laminopathies.
small molecules
2026-08-26 | Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defective nuclear mechanics and transcriptional regulation, yet these mechanisms cannot explain how lamina defects propagate across the cell to produce the complex pathology of laminopathies. Here, we reveal an emerging pathway linking nuclear lamina dysfunction to cytoplasmic reorganization. Using Caenorhabditis elegans EDMD models, we show that disease-linked lamin variants reduce cytoplasmic mesoscale crowding, increase molecular diffusivity, and disrupt nuclear positioning and endoplasmic reticulum architecture, which mirror phenotypes caused by ribosome depletion. Lamin dysfunction also lowers nucleolar fibrillarin levels and ribosome abundance, revealing a nucleolar-ribosomal axis that transmits nuclear defects to the cytoplasm. Loss of the redundant LEM-domain proteins emr-1 and lem-2 phenocopied lamin mutants, indicating that cytoplasmic disorganization is a shared hallmark of EDMD. These findings connect nuclear architecture to whole-cell biophysics and suggest therapeutic strategies aimed at restoring ribosome function.
2026-07-28 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-10-03 | Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis controlling cytoplasmic macromolecular crowding.
Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defects in nuclear mechanics and transcription regulation. Yet these models do not fully explain the complexity of EDMD or other laminopathies. Here, we uncover an emerging pathway linking nuclear lamina defects to the reorganization of cytoplasmic biophysics, revealing how nuclear dysfunction cascades throughout the cell. Using Caenorhabditis elegans EDMD models, we demonstrate that lamin mutations dramatically alter cytoplasmic organization, reducing macromolecular crowding and increasing diffusivity of 40 nm Genetically Encoded Multimeric (GEM) nanoparticles. These striking biophysical changes coincide with nuclear positioning defects and collapsed endoplasmic reticulum architecture, mirroring phenotypes associated with ribosome depletion. We propose a mechanism where mutations in the C. elegans lamin lmn-1 disrupt nucleolar density and ribosome biogenesis, creating a nucleolar-ribosomal axis that propagates defects from the nucleus to the cytoplasm. Genetic interactions between lmn-1 and ribosomes support this regulatory relationship. While individual depletion of other nuclear envelope proteins produces minimal effects, combined loss of the functionally redundant emerin ortholog emr-1 and LEM-domain protein lem-2 phenocopied lmn-1 mutants, demonstrating that cytoplasmic biophysical disruption lies at EDMD's pathogenic core. Our findings establish a paradigm where nuclear lamina defects fundamentally rewire cellular biophysics through nucleolar-ribosomal dysfunction, opening transformative therapeutic avenues for treating laminopathies.
2025-04-27 | iPSC-derived cardiomyocytes and engineered heart tissues reveal suppressed JAK2/STAT3 signaling in LMNA-related emery-dreifuss muscular dystrophy.
LMNA mutation related Emery-Dreifuss muscular dystrophy (LMNA-related EDMD), is a rare genetic disorder often involving life-threatening cardiac complications. However, the molecular links between LMNA mutations and their related EDMD cardiac phenotypes have remained unclear. Here, using EDMD patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we link the LMNA L204P mutation with the pathogenic phenotypes of arrhythmia and contractile dysfunction. Using multi-omics analysis, we then show that LMNA L204P results in decreased chromatin accessibility, leading to the downregulation of JAK2 in EDMD iPSC-CMs. Mechanistically, JAK2/STAT3 signaling pathway suppression in EDMD iPSC-CMs is shown to cause mitochondrial dysfunction and oxidative stress, ultimately resulting in the above phenotypes. Conversely, pharmacological or genetic activation of JAK2/STAT3 signaling effectively rescues both the arrhythmic and contractile dysfunction phenotypes in EDMD iPSC-CMs via improvements in mitochondrial function. In addition, whilst EDMD engineered heart tissues (EHTs) display dysfunctional contractile force generation, this can also be significantly alleviated by STAT3 activation. Taken together, we present chromatin compartment change-mediated JAK2/STAT3 suppression as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating the JAK2/STAT3 signaling pathway may hold the potential to serve as a novel therapeutic strategy for this condition.
proteins
2026-04-17 | WNT5a-Mediated Aberrant Actin Filament Dynamics Drive Cardiac Pathogenic Phenotypes in LMNA-Related Emery-Dreifuss Muscular Dystrophy.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare genetic disorder characterized by early-onset joint contractures, progressive muscle atrophy, and cardiac abnormalities. Patients with EDMD carrying LMNA sequence variations often exhibit severe cardiac manifestations, including frequent atrioventricular block and ventricular tachycardia. Approximately 20% of those patients may ultimately require heart transplantation. The molecular mechanisms by which LMNA sequence variations lead to EDMD remain unknown. Five clinically diagnosed patients with EDMD carrying LMNA sequence variations were recruited. Patient-specific induced pluripotent stem cells (iPSCs) were generated using a nonintegrating Sendai virus. Previously generated iPSCs, derived from 2 healthy donors, were used as controls. The LMNA L204P sequence variation was corrected by genome editing in EDMD iPSC lines to generate isogenic controls. All iPSC-derived cardiomyocytes (iPSC-CMs) were generated using a monolayer-based differentiation protocol. Three-dimensional, strip-format, and force-generating human engineered heart tissues were generated from iPSC-CMs. A knock-in mouse model carrying the Lmna L204P sequence variation was also generated. EDMD-specific iPSC-CMs exhibited a variety of deleterious phenotypes, including disorganized sarcomeres, abnormal nuclear envelope structure, arrhythmias, and contractile dysfunction, when compared with control and gene-corrected iPSC-CMs. Multi-omics analysis further revealed that LMNA directly binds the WNT5A promoter and the Leu204Pro sequence variation reduces chromatin accessibility and WNT5A transcription in EDMD iPSC-CMs. WNT5a (Wnt family member 5a)/RhoA (Ras homolog family member A) signaling inactivation was shown to lead to actin depolymerization and inhibition of actin polymerization in EDMD iPSC-CMs. This results in a deformed nuclear envelope, contractile dysfunction, and impaired trafficking of Cx43 (connexin 43). The impairment of Cx43 trafficking causes reduced distribution of Cx43 at cell-cell borders, contributing to the arrhythmic phenotype in EDMD iPSC-CMs. Pharmacological interventions of exogenous WNT5a supplementation, RhoA activator, or an actin polymerization stabilizer effectively rescued the pathogenic phenotypes of EDMD iPSC-CMs. EDMD engineered heart tissues displayed dysfunctional contractile force generation, which was significantly alleviated by RhoA activator. Lmna L204P heterozygous knock-in mice exhibited impaired cardiac function and developed cardiac arrhythmias in response to sympathetic stress. We present WNT5a-mediated aberrant actin filament dynamics as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating WNT5a/RhoA and stabilizing actin assembly may serve as novel therapeutic strategies for this condition.
2025-06-06 | Cargo recognition of Nesprin-2 by the dynein adapter Bicaudal D2 for a nuclear positioning pathway that is important for neuronal migration.
Nesprin-2 is a subunit of LINC complexes, which span the nuclear envelope and have key roles in mechanotransduction and nuclear positioning during brain and muscle development. Nesprin-2 interacts with the plus-end directed motor kinesin-1 and the dynein adapter Bicaudal D2 (BicD2), which in turn recruits the minus-end directed motor cytoplasmic dynein to position the nucleus during neuronal migration of postmitotic neurons, but the molecular details of these interactions are elusive. Here we present a structural model of a minimal Nesprin-2/BicD2 complex. A structure prediction with a PAE score in the high confidence range was obtained from AlphaFold and experimentally validated by mutagenesis, binding assays and biophysical studies. The core of the binding site is formed by spectrin repeats of Nesprin-2, which form an alpha-helical bundle with the cargo-binding domain of BicD2. The minimal Nesprin-2 fragment also interacts robustly with full-length BicD2. The BicD2-binding site is separated by a ∼65 residue intrinsically disordered linker from the LEWD sequence motif, that acts as kinesin-1 recruitment site, and we propose that both kinesin-1 and BicD2/dynein interact with Nesprin-2 simultaneously. We propose that structurally distinct interactions between BicD2 and its cargo adapters Nesprin-2, Nup358 and Rab6, as well as distinctions in the adjacent kinesin-1 recruiting sites could finetune overall motility for these transport pathways that have important roles in brain and muscle development. Mutations of Nesprin-2 and BicD2 cause devastating brain and muscle developmental diseases, including Emery-Dreifuss Muscular Dystrophy and spinal muscular atrophy, and results may help devise therapies for these diseases.
2023-10-23 | Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty
Clinical frailty affects ∼10% of people over age 65 and is studied in a chronically inflamed (Interleukin-10 knockout; “IL10-KO”) mouse model. Frailty phenotypes overlap the spectrum of diseases (“laminopathies”) caused by mutations in LMNA . LMNA encodes nuclear intermediate filament proteins lamin A and lamin C (“lamin A/C”), important for tissue-specific signaling, metabolism and chromatin regulation. We hypothesized that wildtype lamin A/C associations with tissue-specific partners are perturbed by chronic inflammation, potentially contributing to dysfunction in frailty. To test this idea we immunoprecipitated native lamin A/C and associated proteins from skeletal muscle, hearts and brains of old (21–22 months) IL10-KO versus control C57Bl/6 female mice, and labeled with Tandem Mass Tags for identification and quantitation by mass spectrometry. We identified 502 candidate lamin-binding proteins from skeletal muscle, and 340 from heart, including 62 proteins identified in both tissues. Candidates included frailty phenotype-relevant proteins Perm1 and Fam210a, and nuclear membrane protein Tmem38a, required for muscle-specific genome organization. These and most other candidates were unaffected by IL10-KO, but still important as potential lamin A/C-binding proteins in native heart or muscle. A subset of candidates (21 in skeletal muscle, 30 in heart) showed significantly different lamin A/C-association in an IL10-KO tissue ( p < 0.05), including AldoA and Gins3 affected in heart, and Lmcd1 and Fabp4 affected in skeletal muscle. To screen for binding, eleven candidates plus prelamin A and emerin controls were arrayed as synthetic 20-mer peptides (7-residue stagger) and incubated with recombinant purified lamin A “tail” residues 385–646 under relatively stringent conditions. We detected strong lamin A binding to peptides solvent exposed in Lmcd1, AldoA, Perm1, and Tmem38a, and plausible binding to Csrp3 (muscle LIM protein). These results validated both proteomes as sources for native lamin A/C-binding proteins in heart and muscle, identified four candidate genes for Emery-Dreifuss muscular dystrophy (CSRP3, LMCD1, ALDOA, and PERM1), support a lamin A-interactive molecular role for Tmem38A, and supported the hypothesis that lamin A/C interactions with at least two partners (AldoA in heart, transcription factor Lmcd1 in muscle) are altered in the IL10-KO model of frailty.
2015-11-02 | Nesprin-2 mediated nuclear trafficking and its clinical implications
Nuclear translocation of proteins has a crucial role in the pathogenesis of cancer, Alzheimer disease and viral infections. A complete understanding of nuclear trafficking mechanisms is therefore necessary in order to establish effective intervention strategies. Here we elucidate the role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear transport. Nesprin-2 is an actin-binding nuclear envelope (NE) protein with roles in maintaining nuclear structure and location, regulation of transcription and mechanotransduction. Upon depletion of Nesprin-2 using shRNA, HaCaT cells show abnormal localization of the shuttling proteins BRCA1 and NF-κB. We show that their nuclear transport is unlikely due to the canonical RAN mediated nuclear import, but rather to a RAN independent Ca2+/Calmodulin driven mechanism involving Nesprin-2. We report novel interactions between the actin-binding domain of Nesprin-2 and Calmodulin and between the NLS containing region of BRCA1 and Calmodulin. Strikingly, displacing Nesprins from the NE resulted in increased steady state Ca2+ concentrations in the cytoplasm suggesting a previously unidentified role of Nesprins in Ca2+ regulation. On comparing Nesprin-2 and BRCA1 localization in the ovarian cancer cell lines SKOV-3 and Caov-3, Nesprin-2 and BRCA1 were localized to the NE envelope and the nucleus in SKOV-3, respectively, and to the cytoplasm in Caov-3 cells. Fibroblasts obtained from EDMD5 (Emery Dreifuss muscular dystrophy) patients showed loss of Nesprin-2 from the nuclear envelope, corresponding reduced nuclear localization of BRCA1 and enhanced cytoplasmic Ca2+. Taken together, the data suggests a novel role of Nesprin-2 in Ca2+/Calmodulin mediated nuclear trafficking and provides new insights which can guide future therapies.
2014-12-16 | Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells
During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin-1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-type-specific nuclear positioning during development.
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2026-02-01 | Disruption of Nuclear‐Cytoskeletal Linkage by Coil‐1a LMNA Mutations in Emery–Dreifuss Muscular Dystrophy
ABSTRACT Background Emery–Dreifuss muscular dystrophy (EDMD) is a progressive genetic myopathy that mainly affects the muscles used for movement (skeletal muscles) and the heart (cardiac muscles). The disease is frequently associated with mutations in genes encoding nuclear envelope proteins, most notably LMNA, which encodes lamin A—a critical structural component of the nuclear lamina. Lamin A plays a pivotal role in maintaining nuclear architecture and mechanotransduction. In contrast to most other cell types, nuclei in healthy skeletal muscle fibres are typically localized at the periphery of the myofiber. However, muscle biopsies from EDMD patients often reveal aberrant nuclear morphology and ectopic nuclear positioning, with nuclei clustered or mislocalized toward the centre of the myofiber. Despite these characteristic nuclear abnormalities, the molecular mechanisms underlying nuclear mispositioning in EDMD remain incompletely understood. In particular, the interaction networks between EDMD‐related mutant lamin A and other nuclear and cytoskeletal components that govern nuclear positioning are poorly characterized in the current literature. Methods EDMD‐related lamin A variants (L35V, L38F or Y45C), which are located within the Coil‐1a domain, were overexpressed in RD cells. Mesenchymal stem cells (MSCs) were generated by redifferentiating induced pluripotent stem cells (iPSCs), which were derived from fibroblasts of an EDMD (L35P) patient. To investigate morphological and molecular abnormalities caused by mutations, immunofluorescence imaging, immunoblotting and subcellular fractionation were performed. Functional consequences of these morphological alterations were evaluated by assessing mechanotransduction signalling and cell viability. Results EDMD‐related LMNA mutations (L35V, L38F, Y45C) in the Coil‐1a domain induced multilobular nuclear morphology, accompanied by a decrease in nuclear contour ratio (1.9–3.0‐fold vs. WT, p < 0.0001). Similarly, patient‐derived MSCs (L35P‐MSCs) exhibited a ~2.28‐fold decrease in contour ratio relative to healthy subject‐derived MSCs. Abnormal nuclear shape was associated with structural alterations in nuclear‐cytoskeletal proteins and nuclear positioning regulators. Mechanosensing activity, assessed by YAP1 nuclear translocation, was increased (~1.72‐fold vs. Nor‐CTRL, p < 0.01), and nuclear fragility under physical stress was elevated by ~20% (vs. Nor‐CTRL, p < 0.0001). Treatment with mutation‐specific ASOs in patient‐derived MSCs restored the contour ratio (~1.97‐fold vs. NC‐CTRL, p < 0.01), normalized nuclear‐cytoskeletal organization, reduced mechanosensing response (~1.65‐fold vs. NC‐CTRL, p < 0.01) and decreased nuclear fragility by ~11% (vs. NC‐CTRL, p < 0.0001). Conclusions Our findings indicate that nuclear morphological alterations contribute to the impaired nuclear‐cytoskeletal integrity and nuclear positioning, which are closely linked to cellular mechanics and function. Mutation‐specific ASO treatment alleviated these nuclear defects, suggesting that ASO‐based therapeutic strategies may provide a mutation‐targeted approach to correcting nuclear abnormalities in EDMD.
2025-07-08 | Anti-myogenic and profibrotic effect of serum from patients affected by muscular laminopathies.
Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2) and LMNA-related congenital muscular dystrophy (L-CMD) are caused by mutations in LMNA gene. Both pathologies are characterized by joint contractures, muscle weakness and wasting and cardiac involvement. In the last few years, circulating factors have been proposed to play a critical role in the pathogenesis of these diseases. Based on this consideration, we studied the effect of laminopathic serum on the myogenic differentiation in healthy human myoblasts in culture. We observed impaired myogenesis and increased fibrosis in myoblast cultures conditioned with laminopathic serum and a dramatic increase in the level of profibrotic and proinflammatory cytokines in the cell culture supernatants. These results strongly support the pathogenic role of circulating factors in muscular laminopathies and pave the way to a possible therapeutic strategy.
2025-06-11 | Development of Emerin mRNA Lipid Nanoparticles to Rescue Myogenic Differentiation
Abstract Emery-Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD . Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms, without addressing the underlying cause – lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs have been studied for decades and have recently been used clinically for vaccination and treatment of myriad of diseases. Here, we show treatment of emerin-null myogenic progenitors with LNPs encapsulating emerin mRNA causes robust emerin protein expression that persists for at least 4 days. Treatment of differentiating emerin-null myogenic progenitors with 2.5 pg/cell emerin LNPs significantly improved their differentiation. Toxicity profiling of emerin mRNA LNP (EMD-LNP) dosing shows little toxicity at the effective dose. These data support the potential use of EMD-LNPs as a viable treatment option and establishes its utility for studying EDMD pathology.
2020-05-05 | Emery-Dreifuss muscular dystrophy: focal point nuclear envelope.
Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin and LMNA encoding A-type lamins, proteins of the nuclear envelope. In the past decade, there has been an extraordinary burst of research on the nuclear envelope. Discoveries resulting from this basic research have implications for better understanding the pathogenesis and developing treatments for EDMD. Recent clinical research has confirmed that EDMD is one of several overlapping skeletal muscle phenotypes that can result from mutations in EMD and LMNA with dilated cardiomyopathy as a common feature. Basic research on the nuclear envelope has provided new insights into how A-type lamins and emerin function in force transmission throughout the cell, which may be particularly important in striated muscle. Much of the recent research has focused on the heart and LMNA mutations. Prevalence and outcome studies have confirmed the relative severity of cardiac disease. Robust mouse models of EDMD caused by LMNA mutations has allowed for further insight into pathogenic mechanisms and potentially beneficial therapeutic approaches. Recent clinical and basic research on EDMD is gradually being translated to clinical practice and possibly novel therapies.
2019-09-01 | Pathogenic Abnormal Splicing Due to Intronic Deletions that Induce Biophysical Space Constraint for Spliceosome Assembly
A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5′ splice-site (5′SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5′SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5′SS-branchpoint length in our index EMD case subject defines 45–47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5′SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics. A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5′ splice-site (5′SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5′SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5′SS-branchpoint length in our index EMD case subject defines 45–47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5′SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.
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