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Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures
  1. Johann Böhm1,
  2. Edoardo Malfatti2,3,
  3. Emily Oates4,5,
  4. Kristi Jones4,6,
  5. Guy Brochier2,
  6. Anne Boland7,
  7. Jean-François Deleuze7,
  8. Norma Beatriz Romero2,3,
  9. Jocelyn Laporte1
  1. 1 Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, Illkirch, France
  2. 2 Morphological Unit, Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France
  3. 3 Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  4. 4 Institute for Neuroscience and Muscle Research, Kid’s Research Institute, Children’s Hospital at Westmead, Sydney, New South Wales, Australia
  5. 5 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
  6. 6 Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
  7. 7 Centre National de Recherche en Génomique Humaine (CNRGH), Institut de biologie François Jacob, CEA, Évry, France
  1. Correspondence to Dr Johann Böhm, Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, Illkirch 67404, France; johann{at}


Background The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder.

Objective We aim to contribute to a better understanding of the ASCC1-related disorder.

Methods Here, we provide a clinical, histological and genetic description of three additional ASCC1 families.

Results All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations.

Conclusion Overall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.

  • ASC-1
  • ASCC1
  • myopathy
  • bone fractures
  • TRIP4

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  • Contributors JB, NBR and JFL designed and coordinated the study. JB, EM, KJ, GB, AB and J-FD performed the experiments. EM, EO, KJ and NBR contributed clinical samples, and histological and patient data. JB wrote the manuscript. As the corresponding author JB takes full responsibility for the data, the analyses and interpretation and the conduct of the research.

  • Funding This work was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, GIS IBiSA maladies rares, the France Génomique National infrastructure funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09) and by Fondation Maladies Rares within the frame of the “Myocapture” sequencing project.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Experimentation was performed following institutional IRB-accepted protocols validated by the Comité de Protection des Personnes Est IV (DC-2012–1693).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published online first. In section: ’Exome sequencing identifies mutations in ASCC1', as well as in table 1, the denomination of one of the mutations has been corrected to c.412C>T (p.Arg138*). Figure 1 has also been updated.