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

Feichtinger, René G.; Mucha, Bettina; Hengel, Holger; Orfi, Zakaria; Makowski, Christine; Dort, Junio; D’Anjou, Guy; Nguyen, Thi Tuyet Mai; Buchert, Rebecca; Juenger, Hendrik; Freisinger, Peter; Baumeister, Sarah; Schöser, Benedikt; Ahting, Uwe; Keimer, R.; Nguyen, Cuong; Fabre, Paul; Gauthier, Julie; Miguet, Marguerite; Lopes, Fátima; Alhakeem, Afnan; Alhashem, Amal; Tabarki, Brahim; Kandaswamy, Krishna Kumar; Bauer, Péter; Steinbacher, Peter; Prokisch, Holger; Sturm, Marc; Strom, Tim M.; Ellezam, Benjamin; Mayr, Johannes A.; Schöls, Lüdger; Michaud, Jacques L.; Campeau, Philippe M.; Haack, Tobias B.; Dumont, Nicolas A.

doi:10.1038/s41436-019-0532-z

Cited by 28 publications

(26 citation statements)

References 38 publications

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“…This patient carried a homozygous splice acceptor site mutation in PAX7 c.86-1G > A, r.684_919del (NM_002584.2), which resulted in an exclusion of exon 2 and a premature stop codon in exon 3 (Supplementary Fig. 1, Supplementary Table 3 and 4) 17 . Other less likely pathogenic variants in the autozygous regions are depicted in Supplementary Table 3 and were determined by whole-exome sequencing.…”

Section: Resultsmentioning

confidence: 99%

Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

et al. 2019

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Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.

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Section: Resultsmentioning

confidence: 99%

Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

et al. 2019

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“…Also, Pax3 expression was upregulated. A higher level of PAX3 expression was also observed in the muscles of patients carrying loss of function mutation in PAX7 gene, leading to a myopathy of variable severity [66]. On the other hand, the levels of mRNAs coding the fetal myoblast markers were lower in Pax7−/− teratomas.…”

Section: Discussionmentioning

confidence: 99%

Pax7 as molecular switch regulating early and advanced stages of myogenic mouse ESC differentiation in teratomas

et al. 2020

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Background: Pluripotent stem cells present the ability to self-renew and undergo differentiation into any cell type building an organism. Importantly, a lot of evidence on embryonic stem cell (ESC) differentiation comes from in vitro studies. However, ESCs cultured in vitro do not necessarily behave as cells differentiating in vivo. For this reason, we used teratomas to study early and advanced stages of in vivo ESC myogenic differentiation and the role of Pax7 in this process. Pax7 transcription factor plays a crucial role in the formation and differentiation of skeletal muscle precursor cells during embryonic development. It controls the expression of other myogenic regulators and also acts as an anti-apoptotic factor. It is also involved in the formation and maintenance of satellite cell population. Methods: In vivo approach we used involved generation and analysis of pluripotent stem cell-derived teratomas. Such model allows to analyze early and also terminal stages of tissue differentiation, for example, terminal stages of myogenesis, including the formation of innervated and vascularized mature myofibers. Results: We determined how the lack of Pax7 function affects the generation of different myofiber types. In Pax7 −/− teratomas, the skeletal muscle tissue occupied significantly smaller area, as compared to Pax7+/+ ones. The proportion of myofibers expressing Myh3 and Myh2b did not differ between Pax7+/+ and Pax7−/− teratomas. However, the area of Myh7 and Myh2a myofibers was significantly lower in Pax7−/− ones. Molecular characteristic of skeletal muscles revealed that the levels of mRNAs coding Myh isoforms were significantly lower in Pax7−/− teratomas. The level of mRNAs encoding Pax3 was significantly higher, while the expression of Nfix, Eno3, Mck, Mef2a, and Itga7 was significantly lower in Pax7−/− teratomas, as compared to Pax7+/+ ones. We proved that the number of satellite cells in Pax7−/− teratomas was significantly reduced. Finally, analysis of neuromuscular junction localization in samples prepared with the iDISCO method confirmed that the organization of neuromuscular junctions in Pax7−/− teratomas was impaired.

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“…* and # P < .05, ** and ## P < .01, *** and ### P < .001 4.1 | Steady state in uninjured HTZ muscle Impairment in the SC population has been documented in various neuromuscular disorders as an important component of disease development. [34][35][36][37][38][39][40] In particular, a reduced number of satellite cells have been previously identified in the X-linked form of centronuclear myopathy, also called Myotubular myopathy, due to mutation in myotubularin. 41 We demonstrate a similar reduction in the number of SCs in the gastrocnemius muscle of an AD-CNM animal model, confirming the recent results gained in the Tibialis anterior muscle of this model 22 and suggesting a potential common mechanism for the centronuclear myopathies.…”

Section: Discussionmentioning

confidence: 99%

Satellite cells deficiency and defective regeneration in dynamin 2‐related centronuclear myopathy

2021

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Centronuclear myopathies (CNM) form a group of rare congenital myopathies, clinically and genetically heterogeneous, characterized mainly by muscle weakness. Mutations in several genes have been identified as the cause of X-linked, autosomal recessive, and autosomal dominant forms of inheritance, but mutations in MTM1, BIN1, and DNM2 genes represent most of the reported cases. 1-3 Clinical signals in CNMs vary from severe hypotonia in

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

Cited by 28 publications

References 38 publications

Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

Pax7 as molecular switch regulating early and advanced stages of myogenic mouse ESC differentiation in teratomas

Satellite cells deficiency and defective regeneration in dynamin 2‐related centronuclear myopathy

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