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

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.

SUBMITTER: Bachmann C

PROVIDER: S-EPMC6660981 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Bachmann Christoph C Noreen Faiza F Voermans Nicol C NC Schär Primo L PL Vissing John J Fock Johanna M JM Bulk Saskia S Kusters Benno B Moore Steven A SA Beggs Alan H AH Mathews Katherine D KD Meyer Megan M Genetti Casie A CA Meola Giovanni G Cardani Rosanna R Mathews Emma E Jungbluth Heinz H Muntoni Francesco F Zorzato Francesco F Treves Susan S

Human mutation 20190401 7

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 couplin ...[more]

PMID: 30932294

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Project description:PurposeOsteoarthritis (OA) is a common disease for human beings, characterized by severe inflammation, cartilage degradation, and subchondral bone destruction. However, current therapies are limited to relieving pain or joint replacement and no effective treatment methods have been discovered to improve degenerative changes. Currently, a variety of evidences have indicated that aberrant mechanical stimuli is closely associated with articular joint pathogenesis, while the detailed underlying mechanism remains unelucidated. In the present study, we determined to investigate the impact of excessive high fluid shear stress (FSS) on primary chondrocytes and the underlying epigenetic mechanisms.Materials and methodsPhalloidin staining and EdU staining were used to evaluate cell morphology and viability. The mRNA level and protein level of genes were determined by qPCR, Western blot assay, and immunofluorescence staining. Mechanistic investigation was performed through RNA-sequencing and CUT&Tag sequencing. In vivo, we adopted unilateral anterior crossbites (UAC) mice model to investigate the expression of H3K4me3 and ZBTB20 in aberrant force-related cartilage pathogenesis.ResultsThe results demonstrated that FSS greatly disrupts cell morphology and significantly decreased chondrocyte viability. Aberrant FSS induces remarkable inflammatory mediators production, leading to cartilage degeneration and degradation. In depth mechanistic study showed that FSS results in more than 10-fold upregulation of H3K4me3, and the modulatory effect of H3K4me3 on cartilage was obtained by directly targeting ZBTB20. Furthermore, Wnt signaling was strongly activated in high FSS-induced OA pathogenesis, and the negative impact of ZBTB20 on chondrocytes was also achieved through activating Wnt signaling pathway. Moreover, pharmacological inhibition of H3K4me3 activation by MM-102 or treatment with Wnt pathway inhibitor LF3 could effectively alleviate the destructive effect of FSS on chondrocytes. In vivo UAC mice model validated the dysregulation of H3K4me3 and ZBTB20 in aberrant force-induced cartilage pathogenesis.ConclusionThrough the combination of in vitro FSS model and in vivo UAC model, KMT2B-H3K4me3-ZBTB20 axis was first identified in aberrant FSS-induced cartilage pathogenesis, which may provide evidences for epigenetic-based therapy in the future.

Project description:Background: Selenoprotein N-related myopathies (SEPN1-RMs) are a subset of congenital myopathies caused by mutations of Selenoprotein N gene (SELENON or SEPN1). Clinical phenotype is considered as highly consistent and little attention has been given to the extramuscular abnormalities. Methods: We reported clinical, histopathological, and genetic features of four Chinese patients with SEPN1-RM and performed literature review on delayed respiratory insufficiency and extramuscular involvement. Results: A total of four patients exhibited both the typical and atypical clinical features of SEPN1-RM. The classical manifestations included axial and limb girdle weakness, spinal rigidity, scoliosis, respiratory insufficiency, and multiminicore morphological lesions. However, high interindividual variability was noticed on disease severity, especially the onset of respiratory involvement. Two adult patients postponed respiratory insufficiency to the third decade of life, while two juvenile patients manifested early hypoventilation with puberty exacerbation. As atypical features, extramuscular involvement of weight gain, subcutaneous adipose tissue accumulation, intellectual disability, and mild cardiac changes were observed. Molecular findings revealed three novel mutations of SELENON such as c.1286_1288 del CCT, c.1078_1086dupGGCTACATA, and c.785 G>C. Ten cases with delayed respiratory insufficiency were identified from previous publications. A total of 18 studies described extramuscular abnormalities including joint contractures, alterations of body mass index (BMI), mild cardiac changes, and insulin resistance. Intellectual impairment was extremely rare. Conclusion: SEPN1-RM should be considered as a differential diagnosis in adult patients with delayed respiratory involvement. Extramuscular involvement such as body composition alterations deserves more clinical attention. The novel mutations of SELENON widened the genetic spectrum of patients with SEPN1-RM.

Dataset Information

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

Publications

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

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