René G Feichtinger1, Bettina E Mucha2, Holger Hengel3,4, Zakaria Orfi5, Christine Makowski6, Philippe M Campeau7, Tobias B Haack8,9, Nicolas A Dumont10,11, Junio Dort5, Guy D'Anjou12,13, Thi Tuyet Mai Nguyen5, Rebecca Buchert14, Hendrik Juenger15,16, Peter Freisinger17, Sarah Baumeister18, Benedikt Schoser18, Uwe Ahting19, Reinhard Keimer20, Cam-Tu Emilie Nguyen21, Paul Fabre5, Julie Gauthier21, Marguerite Miguet21, Fátima Lopes21,22, Afnan AlHakeem23, Amal AlHashem24,25, Brahim Tabarki23, Krishna Kumar Kandaswamy26, Peter Bauer14,26, Peter Steinbacher27, Holger Prokisch19,28, Marc Sturm14, Tim M Strom19,28, Benjamin Ellezam29, Johannes A Mayr1, Ludger Schöls3,4, Jacques L Michaud5,12,13. 1. Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria. 2. Division of Medical Genetics, Department of Specialized Medicine, McGill University Hospital Centre, Montreal, QC, Canada. 3. Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 4. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 5. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. 6. Department for Paediatric and Adolescent Medicine, Schwabing Hospital, Technische Universität München, Munich, Germany. 7. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. p.campeau@umontreal.ca. 8. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. Tobias.Haack@med.uni-tuebingen.de. 9. Institute of Human Genetics, Technische Universität München, München, Germany. Tobias.Haack@med.uni-tuebingen.de. 10. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. nicolas.dumont.1@umontreal.ca. 11. School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. nicolas.dumont.1@umontreal.ca. 12. Department of Neurosciences, Université de Montréal, Montreal, QC, Canada. 13. Department of Pediatrics, Université de Montréal, Montreal, QC, Canada. 14. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 15. Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 16. Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany. 17. Kreiskliniken Reutlingen, Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany. 18. Friedrich-Baur-Institute, Department of Neurology, University Clinics Ludwig-Maximilians-University of Munich, Munich, Germany. 19. Institute of Human Genetics, Technische Universität München, München, Germany. 20. Kinderklinik, Stauferklinik, Schwäbisch Gmünd, Germany. 21. CHU Sainte-Justine, Montreal, QC, Canada. 22. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. 23. Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Medical Military City, Military City, Saudi Arabia. 24. Division of Medical Genetics, Department of Pediatrics, Prince Sultan Medical Military City, Military City, Saudi Arabia. 25. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 26. Centogene AG, Rostock, Germany. 27. Department of Biosciences, University of Salzburg, Salzburg, Austria. 28. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 29. Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
Abstract
PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
Authors: Sandra Coppens; Alison M Barnard; Sanna Puusepp; Sander Pajusalu; Katrin Õunap; Dorianmarie Vargas-Franco; Christine C Bruels; Sandra Donkervoort; Lynn Pais; Katherine R Chao; Julia K Goodrich; Eleina M England; Ben Weisburd; Vijay S Ganesh; Sanna Gudmundsson; Anne O'Donnell-Luria; Mait Nigul; Pilvi Ilves; Payam Mohassel; Teepu Siddique; Margherita Milone; Stefan Nicolau; Reza Maroofian; Henry Houlden; Michael G Hanna; Ros Quinlivan; Mehran Beiraghi Toosi; Ehsan Ghayoor Karimiani; Sabine Costagliola; Nicolas Deconinck; Hazim Kadhim; Erica Macke; Brendan C Lanpher; Eric W Klee; Anna Łusakowska; Anna Kostera-Pruszczyk; Andreas Hahn; Bertold Schrank; Ichizo Nishino; Masashi Ogasawara; Rasha El Sherif; Tanya Stojkovic; Isabelle Nelson; Gisèle Bonne; Enzo Cohen; Anne Boland-Augé; Jean-François Deleuze; Yao Meng; Ana Töpf; Catheline Vilain; Christina A Pacak; Marie L Rivera-Zengotita; Carsten G Bönnemann; Volker Straub; Penny A Handford; Isabelle Draper; Glenn A Walter; Peter B Kang Journal: Am J Hum Genet Date: 2021-04-15 Impact factor: 11.025
Authors: Carole Le Coz; David N Nguyen; Chun Su; Brian E Nolan; Amanda V Albrecht; Suela Xhani; Di Sun; Benjamin Demaree; Piyush Pillarisetti; Caroline Khanna; Francis Wright; Peixin Amy Chen; Samuel Yoon; Amy L Stiegler; Kelly Maurer; James P Garifallou; Amy Rymaszewski; Steven H Kroft; Timothy S Olson; Alix E Seif; Gerald Wertheim; Struan F A Grant; Linda T Vo; Jennifer M Puck; Kathleen E Sullivan; John M Routes; Viktoria Zakharova; Anna Shcherbina; Anna Mukhina; Natasha L Rudy; Anna C E Hurst; T Prescott Atkinson; Titus J Boggon; Hakon Hakonarson; Adam R Abate; Joud Hajjar; Sarah K Nicholas; James R Lupski; James Verbsky; Ivan K Chinn; Michael V Gonzalez; Andrew D Wells; Alex Marson; Gregory M K Poon; Neil Romberg Journal: J Exp Med Date: 2021-05-05 Impact factor: 14.307