ArticleNature genetics2024
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
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Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18citing papers in PubMed
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- SRPK3 exacerbates cardiac ischemia/reperfusion injury by regulating KLF3-mTOR/P70 S6K-mediated autophagy.Acta pharmacologica Sinica · 2026Article
- From splicing to disease: the crucial role of serine/arginine protein kinases in cellular regulation.Molecular biology reports · 2026Review
- Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy.Annals of clinical and translational neurology · 2026Article
- Genetic Landscape and Diagnostic Outcomes of UK Patients With Congenital Myopathies and Muscular Dystrophies Over a 10-Year Period.Neurology. Genetics · 2026Article
- Co-occurrence of rare variants implicates gene pairs in cytoskeletal pathways and is associated with increased severity in autism spectrum disorder.Genome biology · 2026Article
- A comprehensive framework for the interpretation of TTN missense variants.Genome medicine · 2026Article
- Decoding SR protein regulation: kinases, phosphatases, and therapeutic targeting strategies.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Alternative splicing dynamics during human cardiac development in vivo and in vitro.Stem cell reports · 2026Article
- Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Biallelic variants in RYR1 and STAC3 are predominant causes of King-Denborough Syndrome in an African cohort.European journal of human genetics : EJHG · 2025Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
- Congenital Titinopathies Linked to Mutations inInternational journal of molecular sciences · 2024Article
- Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.Human molecular genetics · 2024Article
- Inferring disease course from differential exon usage in the wide titinopathy spectrum.Annals of clinical and translational neurology · 2024Article
- Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.Genome medicine · 2024Article
- Congenital LMNA-Related Muscular Dystrophy in Paediatrics: Cardiac Management in Monozygotic Twins.International journal of molecular sciences · 2024Article
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Authors and funding
85 authors at 20 institutions in 13 countries.
Ana TöpfJohn 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.ORCID http://orcid.org/0000-0002-9227-2526
Dan CoxJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0002-5405-6267
Irina T ZaharievaDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
Valeria Di LeoJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Jaakko SarparantaFolkhälsan Research Center, Helsinki, Finland.ORCID http://orcid.org/0000-0002-5497-5255
Per Harald JonsonFolkhälsan Research Center, Helsinki, Finland.ORCID http://orcid.org/0000-0003-2423-359X
Ian M SealySchool of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0002-2890-6635
Andrei SmolnikovSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Richard J WhiteSchool of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0003-1842-412X
Anna ViholaFolkhälsan Research Center, Helsinki, Finland.
Marco SavareseFolkhälsan Research Center, Helsinki, Finland.
Munise MerterogluSchool of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0002-9747-2981
Neha WaliWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Kristen M LaricchiaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cristina VenturiniDivision of Infection and Immunity, University College London, London, UK.
Bas VrolingBio-Prodict, Nijmegen, The Netherlands.
Sarah L StentonProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4071-449X
Beryl B CummingsLaboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padua, Padua, Italy.
Elizabeth HarrisJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0002-4489-3977
Chiara Marini-BettoloJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Jordi Diaz-ManeraJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Matt HendersonMuscle Immunoanalysis Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Rita BarresiIRCCS San Camillo Hospital, Venice, Italy.
Jennifer DuffJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Eleina M EnglandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jane PatrickWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Sundos Al-HusayniThe Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Valerie BiancalanaInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France.
Alan H BeggsThe Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8818-0568
Istvan BodiDepartment of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK.
Shobhana BommireddipalliKids Neuroscience Centre, the Children's Hospital at Westmead, the University of Sydney and the Children's Medical Research Institute, Westmead, New South Wales, Australia.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-5930-2324
Anita CairnsNeurosciences Department, Queensland Children's Hospital, Brisbane, Queensland, Australia.
Mei-Ting ChiewDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, Australia.
Kristl G ClaeysDepartment of Neurology, University Hospitals Leuven, Leuven, Belgium.
Sandra T CooperKids Neuroscience Centre, the Children's Hospital at Westmead, the University of Sydney and the Children's Medical Research Institute, Westmead, New South Wales, Australia.ORCID http://orcid.org/0000-0002-7314-5097
Mark R DavisDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, Australia.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Corrie E ErasmusDepartment of Paediatric Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Amalia Children's Hospital, Nijmegen, The Netherlands.
Mahmoud R FassadWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Casie A GenettiThe Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Carla GrosmannDepartment of Neurology, Rady Children's Hospital University of California San Diego, San Diego, CA, USA.
Heinz JungbluthDepartment of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.ORCID http://orcid.org/0000-0001-6480-1892
Xavière LornageInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France.
Wolfgang N LöscherDepartment of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Edoardo MalfattiAPHP, Neuromuscular Reference Center Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955, INSERM, Creteil, France.
Adnan ManzurDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
Pilar MartíCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.ORCID http://orcid.org/0000-0002-1022-9314
Tiziana E MonginiDepartment of Neurosciences Rita Levi Montalcini, Università degli Studi di Torino, Torino, Italy.
Nuria MuelasCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Atsuko NishikawaDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Anne O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6418-9592
Narumi OgonukiRIKEN BioResource Research Center, Tsukuba, Japan.
Gina L O'GradyStarship Children's Health, Auckland District Health Board, Auckland, New Zealand.
Emily O'HeirProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-7669-8239
Stéphanie PaquayCliniques Universitaires St-Luc, Centre de Référence Neuromusculaire, Université de Louvain, Brussels, Belgium.
Rahul PhadkeDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
Beth A PletcherDivision of Clinical Genetics, Department of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ, USA.
Norma B RomeroNeuromuscular Morphology Unit, Myology Institute, Sorbonne Université, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), GH Pitié-Salpêtrière, Paris, France.
Meyke SchoutenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Snehal ShahDepartment of Neurology, Perth Children's Hospital, Nedlands, Western Australia, Australia.
Izelle SmutsDepartment of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa.
Yves SznajerCenter for Human Genetic, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium.ORCID http://orcid.org/0000-0001-8161-4490
Giorgio TascaJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0003-0849-9144
Robert W TaylorWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0002-7768-8873
Allysa TuiteDivision of Clinical Genetics, Department of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ, USA.ORCID http://orcid.org/0000-0001-7703-3378
Peter Van den BerghCliniques Universitaires St-Luc, Centre de Référence Neuromusculaire, Université de Louvain, Brussels, Belgium.
Grace VanNoyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nicol C VoermansDepartment of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
Julia V WanschitzDepartment of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Elizabeth WraigeEvelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.
Kimihiko YoshimuraDepartment Neurology, Nankoku Hospital, Kochi, Japan.
Emily C OatesSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Osamu NakagawaDepartment of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Ichizo NishinoDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.ORCID http://orcid.org/0000-0001-9452-112X
Jocelyn LaporteInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, Cnrs UMR7104, Université de Strasbourg, Illkirch, France.ORCID http://orcid.org/0000-0001-8256-5862
Juan J VilchezCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.ORCID http://orcid.org/0000-0002-0532-2872
Daniel G MacArthurProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Anna SarkozyDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
Heather J CordellPopulation Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0002-1879-5572
Bjarne UddFolkhälsan Research Center, Helsinki, Finland.
Elisabeth M Busch-NentwichSchool of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
Francesco MuntoniDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
Volker StraubJohn 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.ORCID http://orcid.org/0000-0001-9046-3540
Broad Institute · USNewcastle University · GBGreat Ormond Street Hospital · GBNewcastle upon Tyne Hospitals NHS Foundation Trust · GBUniversity of Helsinki · FIBoston Children's Hospital · USInserm · FRRadboud University Nijmegen · NLCliniques Universitaires Saint-Luc · BEQueen Mary University of London · GBCentre for Biomedical Network Research on Rare Diseases · ESChildren's Medical Research Institute · AUInnsbruck Medical University · ATNational Center of Neurology and Psychiatry · JPNational Institutes of Health · USPathwest Laboratory Medicine · AURutgers, The State University of New Jersey · USSt Thomas' Hospital · GBUniversity of Padua · ITUNSW Sydney · AU
Funding
Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBroad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MMedical Research Council G0800674Medical Research Council MR/S005021/1Medical Research Council MR/W019027/1NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG011755NHGRI NIH HHS UM1 HG008900NICHD NIH HHS U54 HD090255Wellcome Trust
Abstract
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
Indexed as
Muscular DiseasesZebrafishAnimalsConnectinHumansMaleMuscle, SkeletalMutationConnectinTTN protein, human
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