ArticleAmerican journal of human genetics2020
Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 46 citations in OpenAlex.
- Incidence and Prevalence of Congenital Myopathies - A Population-Based Study From Western Sweden.Annals of neurology · 2026Article
- Article
- Distinct impacts of human co-chaperone UNC45 paralogs on Drosophila muscle development and function.Journal of cell science · 2025Article
- Recessive genetic contribution to congenital heart disease in 5,424 probands.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Hsf1 is essential for proteotoxic stress response in smyd1b-deficient embryos and fish survival under heat shock.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Optogenetic induction of mechanical muscle stress identifies myosin regulatory ubiquitin ligase NHL-1 in C. elegans.Nature communications · 2024Article
- UNC-45 assisted myosin folding depends on a conserved FXNature communications · 2024Article
- Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations.Genome medicine · 2024Article
- Next Generation Sequencing and Electromyography Reveal the Involvement of theCurrent issues in molecular biology · 2024Article
- Allelic heterogeneity and abnormal vesicle recycling inFrontiers in molecular neuroscience · 2024Article
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- The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.Genes · 2023Review
- Neuroimaging features of WOREE syndrome: a mini-review of the literature.Frontiers in pediatrics · 2023Review
- The therapeutic effects of physical treatment for patients with hereditary spastic paraplegia: a narrative review.Frontiers in neurology · 2023Review
- Neuroimaging in PRUNE1 syndrome: a mini-review of the literature.Frontiers in neurology · 2023Review
- A ubiquitin fusion reporter to monitor muscle proteostasis inmicroPublication biology · 2023Article
- UCS Chaperone Folding of the Myosin Head: A Function That Evolved before Animals and Fungi Diverged from a Common Ancestor More than a Billion Years Ago.Biomolecules · 2022Review
- UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.The Journal of clinical investigation · 2022Article
- Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study.Acta neuropathologica communications · 2022Article
- Protein profile of fiber types in human skeletal muscle: a single-fiber proteomics study.Skeletal muscle · 2021Article
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Authors and funding
47 authors at 20 institutions in 12 countries.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Carl E KutznerInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
Ying HuNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Xavière LornageInstitut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, CNRS UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch, France.
John RenduCentre Hospitalier Universitaire de Grenoble Alpes, Biochimie Génétique et Moléculaire, Grenoble 38000, France; Grenoble Institut des Neurosciences-INSERM U1216 UGA, Grenoble 38000, France.
Tanya StojkovicCentre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, GHU La Pitié-Salpêtrière, Sorbonne Université, AP-HP, 75013 Paris, France.
Jonathan BaetsFaculty of Medicine, University of Antwerp, 2610 Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, 2650 Antwerp, Belgium.
Sarah B NeuhausNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Jantima TanboonDepartment of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 10700 Bangkok, Thailand; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 187-8502 Tokyo, Japan.
Reza MaroofianDepartment of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Véronique BolducNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Magdalena MroczekJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Stefan ConijnDepartment of Physiology, Amsterdam UMC (location VUmc), 1081 HZ Amsterdam, the Netherlands.
Nancy L KuntzDepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Soledad MongesServicio de Neurología y Servicio de Patologia, Hospital de Pediatría Garrahan, C1245 AAM Buenos Aires, Argentina.
Fabiana LubienieckiServicio de Neurología y Servicio de Patologia, Hospital de Pediatría Garrahan, C1245 AAM Buenos Aires, Argentina.
Riley M McCartyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Katherine R ChaoCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Serena GovernaliDepartment of Physiology, Amsterdam UMC (location VUmc), 1081 HZ Amsterdam, the Netherlands.
Johann BöhmInstitut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, CNRS UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch, France.
Kanokwan BoonyapisitDepartment of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol, University, 10700 Bangkok, Thailand.
Edoardo MalfattiNeurology Department, Raymond-Poincaré teaching hospital, centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, AP-HP, 92380 Garches, France.
Tumtip SangruchiDepartment of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 10700 Bangkok, Thailand.
Iren Horkayne-SzakalyJoint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.
Carola Hedberg-OldforsDepartment of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Satoru NoguchiDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 187-8502 Tokyo, Japan; Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry, 187-8551 Tokyo, Japan.
Sarah DjeddiInstitut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, CNRS UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch, France.
Aritoshi IidaDepartment of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, 187-8551 Tokyo, Japan.
Gabriella di RosaDivision of Child Neurology and Psychiatry, Department of the Adult and Developmental Age Human Pathology, University of Messina, Messina 98125, Italy.
Chiara FiorilloPediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute, 16147 Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
Vincenzo SalpietroPediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute, 16147 Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
Niklas DarinDepartment of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, 41650 Gothenburg, Sweden.
Julien FauréCentre Hospitalier Universitaire de Grenoble Alpes, Biochimie Génétique et Moléculaire, Grenoble 38000, France; Grenoble Institut des Neurosciences-INSERM U1216 UGA, Grenoble 38000, France.
Henry HouldenDepartment of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Anders OldforsDepartment of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
Ichizo NishinoDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 187-8502 Tokyo, Japan; Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry, 187-8551 Tokyo, Japan; Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, 187-8551 Tokyo, Japan.
Willem de RidderFaculty of Medicine, University of Antwerp, 2610 Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, 2650 Antwerp, Belgium.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK.
Wojciech PokrzywaLaboratory of Protein Metabolism in Development and Aging, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
Jocelyn LaporteInstitut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, CNRS UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch, France.
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Norma B RomeroCentre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, GHU La Pitié-Salpêtrière, Sorbonne Université, AP-HP, 75013 Paris, France; Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 75651 Paris, France; Neuromuscular Morphology Unit, Myology Institute, GHU Pitié-Salpêtrière, 75013 Paris, France.
Coen OttenheijmDepartment of Physiology, Amsterdam UMC (location VUmc), 1081 HZ Amsterdam, the Netherlands; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85718, USA.
Thorsten HoppeInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Electronic address: thorsten.hoppe@uni-koeln.de.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: carsten.bonnemann@nih.gov.
National Institutes of Health · USAmsterdam University Medical Centers · NLNational Center of Neurology and Psychiatry · JPUniversity of Gothenburg · SEAssistance Publique – Hôpitaux de Paris · FRCentre National de la Recherche Scientifique · FRGarrahan Hospital · ARGrenoble Institute of Neurosciences · FRIstituto Giannina Gaslini · ITNewcastle University · GBSiriraj Hospital · THUniversity College London · GBAntwerp University Hospital · BEBroad Institute · USCologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · DEDefense Health Agency · USInserm · FRInstitut de Myologie · FRInternational Institute of Molecular and Cell Biology · PLMahidol University · TH
Funding
No grant is acknowledged in the PubMed record.
Abstract
The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
Indexed as
Mutation, MissenseAdolescentAdultAllelesAnimalsCaenorhabditis elegansCaenorhabditis elegans ProteinsExome SequencingFemaleGenetic VariationHumansLoss of Function MutationMaleMolecular ChaperonesMuscle, SkeletalMuscular DiseasesCaenorhabditis elegans ProteinsMolecular ChaperonesMyosinsUNC45B protein, humanunc-45 protein, C elegansC. eleganschaperonecore myopathymusclemyofibrillarmyosinsarcomereUNC-45UNC45B
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