2. Academic Validation
  3. Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy

  • Genet Med. 2019 Nov;21(11):2521-2531. doi: 10.1038/s41436-019-0532-z.
René G Feichtinger # 1,  Bettina E Mucha # 2,  Holger Hengel # 3 4,  Zakaria Orfi # 5,  Christine Makowski # 6,  Junio Dort 5,  Guy D'Anjou 7 8,  Thi Tuyet Mai Nguyen 5,  Rebecca Buchert 9,  Hendrik Juenger 10 11,  Peter Freisinger 12,  Sarah Baumeister 13,  Benedikt Schoser 13,  Uwe Ahting 14,  Reinhard Keimer 15,  Cam-Tu Emilie Nguyen 16,  Paul Fabre 5,  Julie Gauthier 16,  Marguerite Miguet 16,  Fátima Lopes 16 17,  Afnan AlHakeem 18,  Amal AlHashem 19 20,  Brahim Tabarki 18,  Krishna Kumar Kandaswamy 21,  Peter Bauer 9 21,  Peter Steinbacher 22,  Holger Prokisch 14 23,  Marc Sturm 9,  Tim M Strom 14 23,  Benjamin Ellezam 24,  Johannes A Mayr 1,  Ludger Schöls 3 4,  Jacques L Michaud 5 7 8,  Philippe M Campeau # 25,  Tobias B Haack # 26 27,  Nicolas A Dumont # 28 29
Affiliations

Affiliations

  • 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 Department of Neurosciences, Université de Montréal, Montreal, QC, Canada.
  • 8 Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.
  • 9 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • 10 Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 11 Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
  • 12 Kreiskliniken Reutlingen, Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany.
  • 13 Friedrich-Baur-Institute, Department of Neurology, University Clinics Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 14 Institute of Human Genetics, Technische Universität München, München, Germany.
  • 15 Kinderklinik, Stauferklinik, Schwäbisch Gmünd, Germany.
  • 16 CHU Sainte-Justine, Montreal, QC, Canada.
  • 17 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
  • 18 Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Medical Military City, Military City, Saudi Arabia.
  • 19 Division of Medical Genetics, Department of Pediatrics, Prince Sultan Medical Military City, Military City, Saudi Arabia.
  • 20 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 21 Centogene AG, Rostock, Germany.
  • 22 Department of Biosciences, University of Salzburg, Salzburg, Austria.
  • 23 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 24 Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
  • 25 CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. [email protected].
  • 26 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. [email protected].
  • 27 Institute of Human Genetics, Technische Universität München, München, Germany. [email protected].
  • 28 CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. [email protected].
  • 29 School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. [email protected].
  • # Contributed equally.
PMID: 31092906 DOI: 10.1038/s41436-019-0532-z
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.

Keywords

PAX7; muscle stem cell; myoblasts; myopathy; skeletal muscle.

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