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

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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.


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.


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.


These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.

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  1. 1.

    Chi N, Epstein JA. Getting your Pax straight: Pax proteins in development and disease. Trends Genet. 2002;18:41–47.

  2. 2.

    Blake JA, Ziman MR. Pax genes: regulators of lineage specification and progenitor cell maintenance. Development. 2014;141:737–751.

  3. 3.

    Marshall AD, Grosveld GC. Alveolar rhabdomyosarcoma—the molecular drivers of PAX3/7-FOXO1-induced tumorigenesis. Skelet Muscle. 2012;2:25.

  4. 4.

    Mansouri A, Stoykova A, Torres M, Gruss P. Dysgenesis of cephalic neural crest derivatives in Pax7-/- mutant mice. Development. 1996;122:831–838.

  5. 5.

    Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO J. 1991;10:1135–1147.

  6. 6.

    Jostes B, Walther C, Gruss P. The murine paired box gene, Pax7, is expressed specifically during the development of the nervous and muscular system. Mech Dev. 1990;33:27–37.

  7. 7.

    Relaix F, Rocancourt D, Mansouri A, Buckingham M. A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature. 2005;435:948–953.

  8. 8.

    Dumont NA, Bentzinger CF, Sincennes M-C, Rudnicki MA. Satellite cells and skeletal muscle regeneration. Compr Physiol. 2015;5:1027–1059.

  9. 9.

    Bischoff R. The satellite cell and muscle regeneration. In: Engel AG, Franzini-Armstrong C, eds. Myology. 2nd edn. New York: McGraw-Hill; 1994. p. 97–118.

  10. 10.

    Dumont NA, Wang YX, Rudnicki MA. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development. 2015;142:1572–1581.

  11. 11.

    Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA. Pax7 is required for the specification of myogenic satellite cells. Cell. 2000;102:777–786.

  12. 12.

    Kuang S, Chargé SB, Seale P, Huh M, Rudnicki MA. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J Cell Biol. 2006;172:103–113.

  13. 13.

    von Maltzahn J, Jones AE, Parks RJ, Rudnicki MA. Pax7 is critical for the normal function of satellite cells in adult skeletal muscle. Proc Natl Acad Sci U S A. 2013;110:16474–16479.

  14. 14.

    Relaix F, Montarras D, Zaffran S, et al. Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. J Cell Biol. 2006;172:91–102.

  15. 15.

    Kremer LS, Danhauser K, Herebian D, et al. NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood. Am J Hum Genet. 2016;99:894–902.

  16. 16.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760.

  17. 17.

    Dumont N, Rudnicki M. Characterizing satellite cells and myogenic progenitors during skeletal muscle regeneration. In: Pellicciari C, Biggiogera M, eds. Histochemistry of single molecules. Methods in molecular biology. New York: Springer; 2017. p. 179–188.

  18. 18.

    Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.

  19. 19.

    McKinnell IW, Ishibashi J, Le Grand F, et al. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nat Cell Biol. 2008;10:77–84.

  20. 20.

    Alharby E, Albalawi AM, Nasir A, et al. A homozygous potentially pathogenic variant in the PAXBP1 gene in a large family with global developmental delay and myopathic hypotonia. Clin Genet. 2017;92:579–586.

  21. 21.

    Proskorovski-Ohayon R, Kadir R, Michalowski A, et al. PAX7 mutation in a syndrome of failure to thrive, hypotonia, and global neurodevelopmental delay. Hum Mutat. 2017;38:1671–1683.

  22. 22.

    van der Vaart B, van Riel WE, Doodhi H, et al. CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor. Dev Cell. 2013;27:145–160.

  23. 23.

    Cheng L, Desai J, Miranda CJ, et al. Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. Neuron. 2014;82:334–349.

  24. 24.

    Di Gioia SA, Shaaban S, Tüysüz B. Recessive MYF5 mutations cause external ophthalmoplegia, rib, and vertebral anomalies. Am J Hum Genet. 2018;103:115–124.

  25. 25.

    Yamamoto M, Legendre NP, Biswas AA, et al. Loss of MyoD and Myf5 in skeletal muscle stem cells results in altered myogenic programming and failed regeneration. Stem Cell Rep. 2018;10:956–969.

  26. 26.

    Rudnicki MA, Schnegelsberg PNJ, Stead RH, Braun T, Arnold H-H, Jaenisch R. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 1993;75:1351–1359.

  27. 27.

    Sambasivan R, Yao R, Kissenpfennig A, et al. Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development. 2011;138:3647–3656.

  28. 28.

    Fry CS, Lee JD, Mula J, et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med. 2015;21:76–80.

  29. 29.

    Murach KA, White SH, Wen Y, et al. Differential requirement for satellite cells during overload-induced muscle hypertrophy in growing versus mature mice. Skelet Muscle. 2017;7:14.

  30. 30.

    Xu HE, Rould MA, Xu W, Epstein JA, Maas RL, Pabo CO. Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding. Genes Dev. 1999;13:1263–1275.

  31. 31.

    Singh S, Stellrecht CM, Tang HK, Saunders GF. Modulation of PAX6 homeodomain function by the paired domain. J Biol Chem. 2000;275:17306–17313.

  32. 32.

    Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet. 1993;52:455–462.

  33. 33.

    Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet. 1994;6:168–173.

  34. 34.

    Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998;19:83–86.

  35. 35.

    Lammi L, Halonen K, Pirinen S, Thesleff I, Arte S, Nieminen P. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Eur J Hum Genet. 2003;11:866–871.

  36. 36.

    Oustanina S, Hause G, Braun T. Pax7 directs postnatal renewal and propagation of myogenic satellite cells but not their specification. EMBO J. 2004;23:3430–3439.

  37. 37.

    Hirai H, Verma M, Watanabe S, Tastad C, Asakura Y, Asakura A. MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J Cell Biol. 2010;191:347–365.

  38. 38.

    Liu N, Garry GA, Li S, et al. A Twist2-dependent progenitor cell contributes to adult skeletal muscle. Nat Cell Biol. 2017;19:202–213.

  39. 39.

    Giordani L, He GJ, Negroni E, et al. High-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle-Resident Cell Populations. Mol Cell. 2019;74:609–621.

  40. 40.

    Lepper C, Partridge TA, Fan C-M. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development. 2011;138:3639–3646.

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We thank the participants and their families for their participation in this study. This study was supported by the German Bundesministerium für Bildung und Forschung through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ01ZX1405C to T.B.H.) and Horizon2020 through the E-Rare project GENOMIT (01GM1603 and 01GM1207 for H.P. and FWFI2741B26 for J.A.M.) and the Deutsche Forschungsgemeinschaft (SCHO754/52 to L.S. and BA2427/22 to P.B.) as well as the Vereinigung zur Förderung Pädiatrischer Forschung und Fortbildung Salzburg, the EU FP7 Mitochondrial European Educational Training Project (317433 to H.P. and J.A.M.), and the EU Horizon2020 Collaborative Research Project SOUND (633974 to H.P.). N.A.D. is supported by grants from the Fonds de recherche du Québec–Santé (35015), Canadian Institutes of Health Research (388296), Rare Disease Foundation (2301), and CHU Sainte-Justine Foundation. N.A.D. acknowledges the support of ThéCell and Stem Cell Network.

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Correspondence to Philippe M. Campeau MD or Tobias B. Haack MD or Nicolas A. Dumont PhD.

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  • skeletal muscle
  • PAX7
  • myopathy
  • muscle stem cell
  • myoblasts