Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

Autor: Töpf A; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. ana.topf@ncl.ac.uk., Cox D; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Zaharieva IT; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK., Di Leo V; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; Department of Life Sciences, University of Trieste, Trieste, Italy., Sarparanta J; Folkhälsan Research Center, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Jonson PH; Folkhälsan Research Center, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Sealy IM; School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Smolnikov A; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., White RJ; School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Vihola A; Folkhälsan Research Center, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.; Neuromuscular Research Centre, Tampere University and University Hospital, Tampere, Finland., Savarese M; Folkhälsan Research Center, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland., Merteroglu M; School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.; Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padua, Padua, Italy., Wali N; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Laricchia KM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Venturini C; Division of Infection and Immunity, University College London, London, UK., Vroling B; Bio-Prodict, Nijmegen, The Netherlands., Stenton SL; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA., Cummings BB; Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padua, Padua, Italy., Harris E; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.; Northern Genetics Service, Institute of Genetics Medicine, Newcastle upon Tyne, UK., Marini-Bettolo C; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Diaz-Manera J; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Henderson M; Muscle Immunoanalysis Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Barresi R; IRCCS San Camillo Hospital, Venice, Italy., Duff J; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., England EM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Patrick J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Al-Husayni S; The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Biancalana V; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France., Beggs AH; The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Bodi I; Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK., Bommireddipalli S; Kids Neuroscience Centre, the Children's Hospital at Westmead, the University of Sydney and the Children's Medical Research Institute, Westmead, New South Wales, Australia., Bönnemann CG; Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Cairns A; Neurosciences Department, Queensland Children's Hospital, Brisbane, Queensland, Australia., Chiew MT; Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, Australia., Claeys KG; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.; Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, KU Leuven, Leuven, Belgium., Cooper ST; Kids Neuroscience Centre, the Children's Hospital at Westmead, the University of Sydney and the Children's Medical Research Institute, Westmead, New South Wales, Australia., Davis MR; Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, Australia., Donkervoort S; Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Erasmus CE; Department of Paediatric Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Amalia Children's Hospital, Nijmegen, The Netherlands., Fassad MR; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Genetti CA; The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Grosmann C; Department of Neurology, Rady Children's Hospital University of California San Diego, San Diego, CA, USA., Jungbluth H; Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.; Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, UK., Kamsteeg EJ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Lornage X; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France., Löscher WN; Department of Neurology, Medical University Innsbruck, Innsbruck, Austria., Malfatti E; APHP, Neuromuscular Reference Center Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955, INSERM, Creteil, France., Manzur A; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK., Martí P; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.; Neuromuscular Research Group, IIS La Fe, Valencia, Spain., Mongini TE; Department of Neurosciences Rita Levi Montalcini, Università degli Studi di Torino, Torino, Italy., Muelas N; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.; Neuromuscular Research Group, IIS La Fe, Valencia, Spain.; Department of Medicine, Universitat de Valencia, Valencia, Spain.; Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain., Nishikawa A; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan., O'Donnell-Luria A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA., Ogonuki N; RIKEN BioResource Research Center, Tsukuba, Japan., O'Grady GL; Starship Children's Health, Auckland District Health Board, Auckland, New Zealand., O'Heir E; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Paquay S; Cliniques Universitaires St-Luc, Centre de Référence Neuromusculaire, Université de Louvain, Brussels, Belgium., Phadke R; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK., Pletcher BA; Division of Clinical Genetics, Department of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ, USA., Romero NB; Neuromuscular Morphology Unit, Myology Institute, Sorbonne Université, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), GH Pitié-Salpêtrière, Paris, France., Schouten M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Shah S; Department of Neurology, Perth Children's Hospital, Nedlands, Western Australia, Australia., Smuts I; Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa., Sznajer Y; Center for Human Genetic, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium., Tasca G; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Taylor RW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Tuite A; Division of Clinical Genetics, Department of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ, USA., Van den Bergh P; Cliniques Universitaires St-Luc, Centre de Référence Neuromusculaire, Université de Louvain, Brussels, Belgium., VanNoy G; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Voermans NC; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands., Wanschitz JV; Department of Neurology, Medical University Innsbruck, Innsbruck, Austria., Wraige E; Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK., Yoshimura K; Department Neurology, Nankoku Hospital, Kochi, Japan., Oates EC; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., Nakagawa O; Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan., Nishino I; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan., Laporte J; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France., Vilchez JJ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.; Neuromuscular Research Group, IIS La Fe, Valencia, Spain., MacArthur DG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW, Sydney, New South Wales, Australia.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia., Sarkozy A; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK., Cordell HJ; Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Udd B; Folkhälsan Research Center, Helsinki, Finland.; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.; Neuromuscular Research Centre, Tampere University and University Hospital, Tampere, Finland., Busch-Nentwich EM; School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK., Muntoni F; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, UCL & Great Ormond Street Hospital Trust, London, UK., Straub V; John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. volker.straub@ncl.ac.uk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Mar; Vol. 56 (3), pp. 395-407. Date of Electronic Publication: 2024 Mar 01.
DOI: 10.1038/s41588-023-01651-0
Abstrakt: In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3 -/- ; ttn.1 +/- ) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
(© 2024. The Author(s).)
Databáze: MEDLINE
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