Journal article
Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N‐related myopathies
Human mutation, Vol.40(7), pp.962-974
07/2019
DOI: 10.1002/humu.23745
PMCID: PMC6660981
PMID: 30932294
Abstract
Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi‐minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or
RYR1, encoding a protein involved in calcium homeostasis and excitation–contraction coupling. The mechanism by which recessive
SELENON variants cause Multiminicore disease (MmD) is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification, and noncoding RNA expression, to understand the pathomechanism of MmD. We identified biochemical changes that are common in patients harboring recessive
RYR1 and
SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with
RYR1 and
SELENON variants identified >3,500 common aberrantly methylated genes, many of which are involved in calcium signaling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies.
We investigated physiological, biochemical, and epigenetic modifications in muscles of patients with SELENON‐related congenital myopathy. We identified biochemical changes that are common in patients harboring recessive
RYR1 and
SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs), and DNA methyltransferases.
Details
- Title: Subtitle
- Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N‐related myopathies
- Creators
- Christoph Bachmann - Basel University HospitalFaiza Noreen - Genome Plasticity Group, Department of Biomedicine, University of BaselNicol C Voermans - Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical CenterPrimo L Schär - Genome Plasticity Group, Department of Biomedicine, University of BaselJohn Vissing - Copenhagen Neuromuscular Center, Rigshospitalet, University of CopenhagenJohanna M Fock - University Hospital GroningenSaskia Bulk - Service de Génétique, CHU de LiegeBenno Kusters - Radboud University Medical CenterSteven A Moore - Carver College of Medicine, The University of IowaAlan H Beggs - The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical SchoolKatherine D Mathews - Carver College of Medicine, University of IowaMegan Meyer - Carver College of Medicine, The University of IowaCasie A Genetti - The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical SchoolGiovanni Meola - IRCCS Policlinico San Donato MilaneseRosanna Cardani - Laboratory of Muscle Histopathology and Molecular Biology IRCCS‐Policlinico San DonatoEmma Mathews - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen SquareHeinz Jungbluth - Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King’s CollegeFrancesco Muntoni - NIHR Great Ormond Street Hospital Biomedical Research CentreFrancesco Zorzato - Microbiology and Applied Pathology Section, University of FerraraSusan Treves - Microbiology and Applied Pathology Section, University of Ferrara
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.40(7), pp.962-974
- DOI
- 10.1002/humu.23745
- PMID
- 30932294
- PMCID
- PMC6660981
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Number of pages
- 13
- Grant note
- Swiss National Science Foundation OPO‐Stiftung NIH Clinical Center (R01 AR044345; USA) Fondazione Malattie Miotoniche FSRMM M.U.R.S.T Muscular Dystrophy Association (MDA383249) Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF 31003A‐169316) NeRAB
- Language
- English
- Date published
- 07/2019
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984046821402771
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