0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

      research-article
      1 , 2 , 2 , 3 , 2 , 1 , 2 , 2 , 4 , 2 , 2 , 2 , 5 , 5 , 1 , 2 , 2 , 3 , 2 , 1 , 2 , 2 , 8 , 3 , 7 , 8 , 9 , 10 , 1 , 2 , 6 , 1 , 2 , 11 , 12 , 3 , 1 , 2 , 11 , 13 ,
      Acta Neuropathologica
      Springer Berlin Heidelberg
      X-linked myotubular myopathy, Congenital myopathies, Epigenetics, Drug discovery

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00401-022-02468-7.

          Related collections

          Most cited references68

          • Record: found
          • Abstract: found
          • Article: not found

          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction

            Background Choosing appropriate primers is probably the single most important factor affecting the polymerase chain reaction (PCR). Specific amplification of the intended target requires that primers do not have matches to other targets in certain orientations and within certain distances that allow undesired amplification. The process of designing specific primers typically involves two stages. First, the primers flanking regions of interest are generated either manually or using software tools; then they are searched against an appropriate nucleotide sequence database using tools such as BLAST to examine the potential targets. However, the latter is not an easy process as one needs to examine many details between primers and targets, such as the number and the positions of matched bases, the primer orientations and distance between forward and reverse primers. The complexity of such analysis usually makes this a time-consuming and very difficult task for users, especially when the primers have a large number of hits. Furthermore, although the BLAST program has been widely used for primer target detection, it is in fact not an ideal tool for this purpose as BLAST is a local alignment algorithm and does not necessarily return complete match information over the entire primer range. Results We present a new software tool called Primer-BLAST to alleviate the difficulty in designing target-specific primers. This tool combines BLAST with a global alignment algorithm to ensure a full primer-target alignment and is sensitive enough to detect targets that have a significant number of mismatches to primers. Primer-BLAST allows users to design new target-specific primers in one step as well as to check the specificity of pre-existing primers. Primer-BLAST also supports placing primers based on exon/intron locations and excluding single nucleotide polymorphism (SNP) sites in primers. Conclusions We describe a robust and fully implemented general purpose primer design tool that designs target-specific PCR primers. Primer-BLAST offers flexible options to adjust the specificity threshold and other primer properties. This tool is publicly available at http://www.ncbi.nlm.nih.gov/tools/primer-blast.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Efficient proximity labeling in living cells and organisms with TurboID

              Protein interaction networks and protein compartmentalization underlie all signaling and regulatory processes in cells. Enzyme-catalyzed proximity labeling (PL) has emerged as a new approach to study the spatial and interaction characteristics of proteins in living cells. However, current PL methods require over 18 hour labeling times or utilize chemicals with limited cell permeability or high toxicity. We used yeast display-based directed evolution to engineer two promiscuous mutants of biotin ligase, TurboID and miniTurbo, which catalyze PL with much greater efficiency than BioID or BioID2, and enable 10-minute PL in cells with non-toxic and easily deliverable biotin. Furthermore, TurboID extends biotin-based PL to flies and worms.
                Bookmark

                Author and article information

                Contributors
                james.dowling@sickkids.ca
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                17 July 2022
                17 July 2022
                2022
                : 144
                : 3
                : 537-563
                Affiliations
                [1 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Molecular Genetics, , University of Toronto, ; Toronto, ON M5S 1A1 Canada
                [2 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Program for Genetics and Genome Biology, , The Hospital for Sick Children, ; 555 University Ave, Toronto, ON M5G 0A4 Canada
                [3 ]GRID grid.414295.f, ISNI 0000 0004 0638 3479, Institute of Cardiovascular and Metabolic Diseases (I2MC), , INSERM, UMR-S U1297 and University of Toulouse III, CHU-Rangueil, ; Toulouse, France
                [4 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Institute of Medical Sciences, , University of Toronto, ; Toronto, ON M5S 1A1 Canada
                [5 ]GRID grid.15781.3a, ISNI 0000 0001 0723 035X, Institut de Pharmacologie Et Biologie Structurale (IPBS), , Université de Toulouse, CNRS, UPS, ; Toulouse, France
                [6 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Program for Genetics and Genome Biology, , The Hospital for Sick Children, ; Toronto, ON M5G 0A4 Canada
                [7 ]GRID grid.411175.7, ISNI 0000 0001 1457 2980, Laboratoire d’Hématologie, , Centre Hospitalier Universitaire (CHU) de Toulouse, ; Toulouse Cedex, France
                [8 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, , Boston Children’s Hospital, Harvard Medical School, ; Boston, MA USA
                [9 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, , NIH, ; Bethesda, MD USA
                [10 ]GRID grid.83440.3b, ISNI 0000000121901201, Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, , University College London, ; London, UK
                [11 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Paediatrics, , University of Toronto, ; Toronto, ON M5S 1A1 Canada
                [12 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Division of Clinical and Metabolic Genetics, , The Hospital for Sick Children, ; Toronto, ON M5G 0A4 Canada
                [13 ]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Division of Neurology, , The Hospital for Sick Children, ; Toronto, ON M5G 0A4 Canada
                Author information
                http://orcid.org/0000-0002-3984-4169
                Article
                2468
                10.1007/s00401-022-02468-7
                9381459
                35844027
                63359afc-74e0-4120-be50-197b9afd1fe1
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 March 2022
                : 4 July 2022
                : 4 July 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000033, Institute of Musculoskeletal Health and Arthritis;
                Award ID: 136867
                Award ID: 153056
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: R21AR074006
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000658, Myotubular Trust;
                Funded by: FundRef http://dx.doi.org/10.13039/100005202, Muscular Dystrophy Association;
                Award ID: MDA602235
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100002104, Joshua Frase Foundation;
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2022

                Neurology
                x-linked myotubular myopathy,congenital myopathies,epigenetics,drug discovery
                Neurology
                x-linked myotubular myopathy, congenital myopathies, epigenetics, drug discovery

                Comments

                Comment on this article