Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

Sandra Donkervoort; Carl E Kutzner; Ying Hu; Xavière Lornage; John Rendu; Tanya Stojkovic; Jonathan Baets; Sarah B Neuhaus; Jantima Tanboon; Reza Maroofian; Véronique Bolduc; Magdalena Mroczek; Stefan Conijn; Nancy L Kuntz; Ana Töpf; Soledad Monges; Fabiana Lubieniecki; Riley M McCarty; Katherine R Chao; Serena Governali; Johann Böhm; Kanokwan Boonyapisit; Edoardo Malfatti; Tumtip Sangruchi; Iren Horkayne-Szakaly; Carola Hedberg-Oldfors; Stephanie Efthymiou; Satoru Noguchi; Sarah Djeddi; Aritoshi Iida; Gabriella di Rosa; Chiara Fiorillo; Vincenzo Salpietro; Niklas Darin; Julien Fauré; Henry Houlden; Anders Oldfors; Ichizo Nishino; Willem de Ridder; Volker Straub; Wojciech Pokrzywa; Jocelyn Laporte; A Reghan Foley; Norma B Romero; Coen Ottenheijm; Thorsten Hoppe; Carsten G Bönnemann

doi:10.1016/j.ajhg.2020.11.002

Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

Am J Hum Genet. 2020 Dec 3;107(6):1078-1095. doi: 10.1016/j.ajhg.2020.11.002. Epub 2020 Nov 19.

Authors

Sandra Donkervoort¹, Carl E Kutzner², Ying Hu¹, Xavière Lornage³, John Rendu⁴, Tanya Stojkovic⁵, Jonathan Baets⁶, Sarah B Neuhaus¹, Jantima Tanboon⁷, Reza Maroofian⁸, Véronique Bolduc¹, Magdalena Mroczek⁹, Stefan Conijn¹⁰, Nancy L Kuntz¹¹, Ana Töpf⁹, Soledad Monges¹², Fabiana Lubieniecki¹², Riley M McCarty¹, Katherine R Chao¹³, Serena Governali¹⁰, Johann Böhm³, Kanokwan Boonyapisit¹⁴, Edoardo Malfatti¹⁵, Tumtip Sangruchi¹⁶, Iren Horkayne-Szakaly¹⁷, Carola Hedberg-Oldfors¹⁸, Stephanie Efthymiou⁸, Satoru Noguchi¹⁹, Sarah Djeddi³, Aritoshi Iida²⁰, Gabriella di Rosa²¹, Chiara Fiorillo²², Vincenzo Salpietro²², Niklas Darin²³, Julien Fauré⁴, Henry Houlden⁸, Anders Oldfors¹⁸, Ichizo Nishino²⁴, Willem de Ridder⁶, Volker Straub²⁵, Wojciech Pokrzywa²⁶, Jocelyn Laporte³, A Reghan Foley¹, Norma B Romero²⁷, Coen Ottenheijm²⁸, Thorsten Hoppe²⁹, Carsten G Bönnemann³⁰

Affiliations

¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
² Institute 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.
³ Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, CNRS UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch, France.
⁴ Centre Hospitalier Universitaire de Grenoble Alpes, Biochimie Génétique et Moléculaire, Grenoble 38000, France; Grenoble Institut des Neurosciences-INSERM U1216 UGA, Grenoble 38000, France.
⁵ Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, GHU La Pitié-Salpêtrière, Sorbonne Université, AP-HP, 75013 Paris, France.
⁶ Faculty 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.
⁷ Department 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.
⁸ Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁹ John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
¹⁰ Department of Physiology, Amsterdam UMC (location VUmc), 1081 HZ Amsterdam, the Netherlands.
¹¹ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹² Servicio de Neurología y Servicio de Patologia, Hospital de Pediatría Garrahan, C1245 AAM Buenos Aires, Argentina.
¹³ Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁴ Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol, University, 10700 Bangkok, Thailand.
¹⁵ Neurology Department, Raymond-Poincaré teaching hospital, centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France, AP-HP, 92380 Garches, France.
¹⁶ Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 10700 Bangkok, Thailand.
¹⁷ Joint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.
¹⁸ Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
¹⁹ Department 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.
²⁰ Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, 187-8551 Tokyo, Japan.
²¹ Division of Child Neurology and Psychiatry, Department of the Adult and Developmental Age Human Pathology, University of Messina, Messina 98125, Italy.
²² Pediatric 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.
²³ Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, 41650 Gothenburg, Sweden.
²⁴ Department 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.
²⁵ John 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.
²⁶ Laboratory of Protein Metabolism in Development and Aging, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
²⁷ Centre 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.
²⁸ Department of Physiology, Amsterdam UMC (location VUmc), 1081 HZ Amsterdam, the Netherlands; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85718, USA.
²⁹ Institute 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: [email protected].
³⁰ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

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.

Keywords: C. elegans; UNC-45; UNC45B; chaperone; core myopathy; muscle; myofibrillar; myosin; sarcomere.

MeSH terms

Adolescent
Adult
Alleles
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins / genetics*
Caenorhabditis elegans Proteins / physiology*
Exome Sequencing
Female
Genetic Variation
Humans
Loss of Function Mutation
Male
Molecular Chaperones / genetics*
Molecular Chaperones / physiology*
Muscle, Skeletal / pathology
Muscular Diseases / genetics*
Mutation, Missense*
Myofibrils
Myosins
Sarcomeres / metabolism
Sequence Analysis, RNA
Transgenes
Young Adult

Substances

Caenorhabditis elegans Proteins
Molecular Chaperones
UNC45B protein, human
unc-45 protein, C elegans
Myosins