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

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...

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Bibliographic Details
Published in:	Human mutation Vol. 40; no. 7; pp. 962 - 974
Main Authors:	Bachmann, Christoph, Noreen, Faiza, Voermans, Nicol C., Schär, Primo L., Vissing, John, Fock, Johanna M., Bulk, Saskia, Kusters, Benno, Moore, Steven A., Beggs, Alan H., Mathews, Katherine D., Meyer, Megan, Genetti, Casie A., Meola, Giovanni, Cardani, Rosanna, Mathews, Emma, Jungbluth, Heinz, Muntoni, Francesco, Zorzato, Francesco, Treves, Susan
Format:	Journal Article Web Resource
Language:	English
Published:	United States Hindawi Limited 01-07-2019 John Wiley and Sons Inc
Subjects:	Adolescent Calcium homeostasis Calcium signalling Cells, Cultured Child Child, Preschool Congenital diseases congenital myopathies Contraction CpG Islands Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferases - genetics DNA Methylation Drug delivery Endoplasmic reticulum Epigenesis, Genetic Epigenetics excitation–contraction coupling gene expression Genetics & genetic processes Génétique & processus génétiques Histone Code Histone Deacetylases - genetics Homeostasis Humans Life sciences Muscle Proteins - genetics Muscular Diseases - congenital Muscular Diseases - genetics Neuromuscular diseases Ribonucleic acid RNA RNA modification ryanodine receptor Ryanodine Receptor Calcium Release Channel - genetics Ryanodine receptors Sciences du vivant Selenoproteins - genetics Skeletal muscle Whole Genome Sequencing congenital myopathies ryanodine receptor excitation-contraction coupling epigenetics gene expression
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-85063687545
ISSN:	1059-7794 1098-1004 1098-1004
DOI:	10.1002/humu.23745