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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121961 | GEO | 2019/06/27

REPOSITORIES: GEO

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Project description:<p>Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an <i>RYR1</i> variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. </p>

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

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