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Genet Med. 2019 Nov;21(11):2521-2531. doi: 10.1038/s41436-019-0532-z. Epub 2019 May 16.

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

Author information

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. p.campeau@umontreal.ca.
26
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. Tobias.Haack@med.uni-tuebingen.de.
27
Institute of Human Genetics, Technische Universität München, München, Germany. Tobias.Haack@med.uni-tuebingen.de.
28
CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada. nicolas.dumont.1@umontreal.ca.
29
School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. nicolas.dumont.1@umontreal.ca.

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

PMID:
31092906
DOI:
10.1038/s41436-019-0532-z

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