Article (Scientific journals)
Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies
Bachmann, C.; Noreen, F.; Voermans, N. C. et al.
2019In Human Mutation
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Abstract :
[en] 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. © 2019 Wiley Periodicals, Inc.
Disciplines :
Genetics & genetic processes
Author, co-author :
Bachmann, C.;  Department of Biomedicine, Basel University Hospital, Basel, Switzerland, Departments of Anesthesia, Basel University Hospital, Basel, Switzerland
Noreen, F.;  Genome Plasticity Group, Department of Biomedicine, University of Basel, Basel, Switzerland
Voermans, N. C.;  Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
Schär, P. L.;  Genome Plasticity Group, Department of Biomedicine, University of Basel, Basel, Switzerland
Vissing, J.;  Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Fock, J. M.;  Department of Neurology, University Hospital Groningen, Groningen, Netherlands
BULK, Saskia ;  Centre Hospitalier Universitaire de Liège - CHU > Unilab > Clinique de génétique
Kusters, B.;  Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
Moore, S. A.;  Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa, IA, United States
Beggs, A. H.;  Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
Mathews, K. D.;  Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa, IA, United States, Department of Neurology, Carver College of Medicine, University of Iowa, Iowa, IA, United States
Meyer, M.;  Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa, IA, United States
Genetti, C. A.;  Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
Meola, G.;  Department of Biomedical Sciences for Health, University of Milan, Milan, Italy, Department of Neurology, IRCCS Policlinico San Donato Milanese, Milan, Italy
Cardani, R.;  Laboratory of Muscle Histopathology and Molecular Biology IRCCS-Policlinico San Donato, Milan, Italy
Mathews, E.;  MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
Jungbluth, H.;  Department of Paediatric Neurology, Neuromuscular Service, Evelina Children’s Hospital, St. Thomas’ Hospital, London, United Kingdom, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom, Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King’s College, London, United Kingdom
Muntoni, F.;  Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL, Institute of Child Health, London, United Kingdom, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
Zorzato, F.;  Department of Biomedicine, Basel University Hospital, Basel, Switzerland, Departments of Anesthesia, Basel University Hospital, Basel, Switzerland, Department of Life Sciences, Microbiology and Applied Pathology Section, University of Ferrara, Ferrara, Italy
Treves, S.;  Department of Biomedicine, Basel University Hospital, Basel, Switzerland, Departments of Anesthesia, Basel University Hospital, Basel, Switzerland, Department of Life Sciences, Microbiology and Applied Pathology Section, University of Ferrara, Ferrara, Italy
More authors (10 more) Less
Language :
English
Title :
Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies
Publication date :
2019
Journal title :
Human Mutation
ISSN :
1059-7794
eISSN :
1098-1004
Publisher :
John Wiley and Sons Inc.
Peer reviewed :
Peer Reviewed verified by ORBi
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since 07 January 2020

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