ArticleEBioMedicine2020
A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism.
Article in EBioMedicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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27 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome.Communications biology · 2024Pooled it
- TRIC-A Loss Sensitizes the Heart to β-Adrenergic Stress and Drives Cardiomyocyte Death and Fibrosis.Biomolecules · 2026Article
- Comparative Analysis of Splicing Alterations in Three Muscular Dystrophies.Biomedicines · 2025Article
- Tubular Lamin- and Emerin-Lined Nuclear Envelope Invaginations Isolate Chromatin Domains for Gene Expression Regulation.Sub-cellular biochemistry · 2025Review
- Pairing Lamin B1-DamID and Immuno-3D-FISH to Resolve and Verify Peripheral Genome Organization of Adipogenesis.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Article
- Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies.Biomolecules · 2023Review
- Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees.Human molecular genetics · 2023Article
- Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty.Frontiers in cell and developmental biology · 2023Article
- Genome-wide analysis of a cellular exercise model based on electrical pulse stimulation.Scientific reports · 2022Article
- Multisystem Proteinopathy Due toGenes · 2022Review
- Nuclear envelope transmembrane proteins involved in genome organization are misregulated in myotonic dystrophy type 1 muscle.Frontiers in cell and developmental biology · 2022Article
- Nuclear organization and dynamics: The final Frontier for understanding genome regulation.Frontiers in cell and developmental biology · 2022Article
- Evolution and diversification of the nuclear envelope.Nucleus (Austin, Tex.) · 2021Article
- The Role of POPDC Proteins in Cardiac Pacemaking and Conduction.Journal of cardiovascular development and disease · 2021Review
- The Diverse Cellular Functions of Inner Nuclear Membrane Proteins.Cold Spring Harbor perspectives in biology · 2021Review
- Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins.International journal of molecular sciences · 2021Review
- Review
- TRIC-A regulates intracellular CaPflugers Archiv : European journal of physiology · 2021Review
- The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization.Nature communications · 2021Article
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundAs genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation.
methodsA primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates - other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype.
findingsTwenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation.
interpretationOur multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases.
fundingThe Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme "Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)".
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