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      Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

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          Abstract

          Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3’-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to trans-dysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.

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          Chapter 11: Genome-Wide Association Studies

          Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.
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            Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.

            Using positional cloning strategies, we have identified a CTG triplet repeat that undergoes expansion in myotonic dystrophy patients. This sequence is highly variable in the normal population. PCR analysis of the interval containing this repeat indicates that unaffected individuals have been 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat containing segment up to several kilobase pairs. The CTG repeat is transcribed and is located in the 3' untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy. This mRNA encodes a polypeptide that is a member of the protein kinase family.
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              Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease.

              Inhibition of muscleblind-like (MBNL) activity due to sequestration by microsatellite expansion RNAs is a major pathogenic event in the RNA-mediated disease myotonic dystrophy (DM). Although MBNL1 and MBNL2 bind to nascent transcripts to regulate alternative splicing during muscle and brain development, another major binding site for the MBNL protein family is the 3' untranslated region of target RNAs. Here, we report that depletion of Mbnl proteins in mouse embryo fibroblasts leads to misregulation of thousands of alternative polyadenylation events. HITS-CLIP and minigene reporter analyses indicate that these polyadenylation switches are a direct consequence of MBNL binding to target RNAs. Misregulated alternative polyadenylation also occurs in skeletal muscle in a mouse polyCUG model and human DM, resulting in the persistence of neonatal polyadenylation patterns. These findings reveal an additional developmental function for MBNL proteins and demonstrate that DM is characterized by misregulation of pre-mRNA processing at multiple levels.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draft
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Data curationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Resources
                Role: ConceptualizationRole: Resources
                Role: Conceptualization
                Role: ConceptualizationRole: Resources
                Role: ConceptualizationRole: ResourcesRole: Writing – Review & Editing
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Project administrationRole: SupervisionRole: Validation
                Role: ConceptualizationRole: Data curationRole: Project administrationRole: SupervisionRole: Writing – Review & Editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2020
                14 April 2020
                : 15
                : 4
                : e0231000
                Affiliations
                [1 ] Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
                [2 ] School of Computing Science, University of Glasgow, Glasgow, United Kingdom
                [3 ] Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
                [4 ] Department of Genetics, University of Texas, MD Anderson Cancer Center, Houston, TX, United States of America
                [5 ] Laboratory of Human Genetics, CHUL Medical Research Centre, University of Laval, Quebec City, QC, Canada
                [6 ] Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University, Munich, Germany
                [7 ] Department of Pediatrics, Division of Neurology, Cincinnati Children’s Hosptial, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America
                [8 ] VA Medical Center, Houston, Texas, United States of America
                [9 ] University of Rochester, Medical Center School of Medicine and Dentistry, Rochester, New York, United States of America
                University of Valencia, SPAIN
                Author notes

                Competing Interests: Adam Kurkiewicz Declares ownership of Illumina and PacBio shares. Anneli Cooper Has served on a Scientific Advisory Board for AstraZeneca (Trypanosomiasis). Sarah Cumming None declared Berit Adam None declared Ralf Krahe None declared. Jack Puymirat None declared Benedikt Schoser Benedikt Schoser is member of the Neuromuscular advisory board of Audentes Therapeutics, USA, and Scientific advisory of Nexien BioPharm, USA. He received speaker honoraria from Sanofi Genzyme, Amicus Therapeutics, Lupin Pharmaceuticals, and Kedrion. He received an unrestricted research grant from Sanofi Genzyme USA (2016-2019), Greenovation FRG (2017-2020), and from the Marigold foundation (2014) Lubov Timchenko None declared. Tetsuo Ashizawa 1. My wife has stocks and stock options of BIOPATH Holdings, Inc. 2. One US and international patent approved. 3. Grants from NIH, the Myotonic Dystrophy Foundation, the National Ataxia Foundation and Biogen. 4. I am a member of the advisory board for the National Ataxia Foundation and that for the Myotonic Dystrophy Foundation. Simon Rogers None declared John McClure None declared Darren G Monckton Professor Monckton has been a scientific consultant and/or received an honoraria or stock options from Biogen Idec, AMO Pharma, Charles River, Vertex Pharmaceuticals, Triplet Therapeutics, LoQus23, BridgeBio, Small Molecule RNA and Lion Therapeutics. Professor Monckton also had a research contract with AMO Pharma and CHDI has received research grants from the European Union, European Huntington Disease Network, National Institute of Health, Muscular Dystrophy UK and the Myotonic Dystrophy Support Group. Professor Monckton is on the Scientific Advisory Board of the Myotonic Dystrophy Foundation, is a scientific advisor to the Myotonic Dystrophy Support Group and is a vice president of Muscular Dystrophy UK. Charles Thornton Dr. Thornton has received sponsored research support from Ionis Pharmaceuticals, Biogen, Genzyme, and Dyne Therapeutics, and research grants from the National Institutes of Health, Food and Drug Administration, Muscular Dystrophy Association, and Myotonic Dystrophy Foundation. Dr Thornton has served on the Scientific Advisory Board for Dyne Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                [¤]

                Current address: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom

                Author information
                http://orcid.org/0000-0002-4806-9168
                http://orcid.org/0000-0002-1159-142X
                http://orcid.org/0000-0003-3578-4477
                Article
                PONE-D-19-24916
                10.1371/journal.pone.0231000
                7156058
                32287265
                02dd6652-af6f-4483-80c5-77c3cf01c5f8
                © 2020 Kurkiewicz et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 September 2019
                : 13 March 2020
                Page count
                Figures: 4, Tables: 4, Pages: 19
                Funding
                Sample collection and initial data analysis were funded by the Marigold Foundation in the form of international collaboration "Dystrophia Myotonica Biomarker Discovery Initiative". The sponsors played active role in the study design and data collection, by liaising with clinicians contributing muscle and blood samples, making arrangements with the company, which carried out the microarray work, and carrying out the initial data analysis. The sponsors played no role in preparation of the manuscript or a decision to publish.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Medicine and Health Sciences
                Clinical Genetics
                Genetic Diseases
                Myotonic Dystrophy
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Forecasting
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Forecasting
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Microarrays
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Muscle Analysis
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Linear Regression Analysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Regression Analysis
                Linear Regression Analysis
                Biology and life sciences
                Genetics
                Gene expression
                RNA processing
                Alternative Splicing
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                RNA processing
                Alternative Splicing
                Custom metadata
                All data has been submitted to Array Express and is publicly available as E-MTAB-7983: https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-7983/.

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