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

ABSTRACT: Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related Multiminicore Disease

PROVIDER: PRJNA501797 | ENA |

REPOSITORIES: ENA

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

Project description:Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and mainly caused by mutations in several genes including RYR1, TTN, MYH7 and SELENON4-6. Recessive mutations in either RYR1, encoding a protein involved in calcium homeostasis and excitation–contraction coupling (ECC) or SELENON (previously known as SEPN1), encoding the endoplasmic reticulum glycoprotein selenoprotein N, being the most common identifiable causes of multiminicore disease (MmD). Although recessive SELENON mutations are causative of MmD, the mechanism by which they alter muscle function is still unclear. Here, we extensively investigated skeletal muscle physiological, biochemical and epigenetic modifications in order to understand the pathomechanism of disease. Epigenetic changes including DNA methylation, histone modification and non coding RNA expression are now recognized as playing a major role in the pathophysiology of many human diseases including cancer, Rett, Prader-Willi, Angelmann syndromes, and many more. In the present investigation we found several modifications that are common between patients harbouring recessive RYR1 and SELENON mutations, including depletion of RYR1, ATP2B2, STAC3 and ATP2A1 transcripts, and increased levels of class II HDACs and DNA methyltransferases. Our findings provide insights to design new molecularly based strategies for drug targeting in patients with congenital myopathies characterized by reduced RyR1 protein content.

2019-06-27 | GSE121961 | GEO

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

Project description: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.

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Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

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Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia II

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