Format

Send to

Choose Destination
Hum Mutat. 2019 Apr 1. doi: 10.1002/humu.23745. [Epub ahead of print]

Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies.

Author information

1
Department of Biomedicine, Basel University Hospital, Basel, Switzerland.
2
Departments of Anesthesia, Basel University Hospital, Basel, Switzerland.
3
Genome Plasticity Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
4
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Department of Neurology, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
6
Department of Neurology, University Hospital Groningen, Groningen, The Netherlands.
7
Department of Human Genetics, Service de Génétique, CHU de Liege, Liege, Belgium.
8
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
9
Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa, Iowa.
10
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
11
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa, Iowa.
12
Department of Neurology, Carver College of Medicine, University of Iowa, Iowa, Iowa.
13
Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
14
Department of Neurology, IRCCS Policlinico San Donato Milanese, Milan, Italy.
15
Laboratory of Muscle Histopathology and Molecular Biology IRCCS-Policlinico San Donato, Milan, Italy.
16
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
17
Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St. Thomas' Hospital, London, UK.
18
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
19
Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.
20
Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Diseases, UCL, Institute of Child Health, London, UK.
21
NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.
22
Department of Life Sciences, Microbiology and Applied Pathology Section, University of Ferrara, Ferrara, Italy.

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.

KEYWORDS:

congenital myopathies; epigenetics; excitation-contraction coupling; gene expression; ryanodine receptor

PMID:
30932294
DOI:
10.1002/humu.23745

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center