The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease

Hum Mol Genet. 2016 Apr 15;25(8):1559-73. doi: 10.1093/hmg/ddw033. Epub 2016 Feb 9.


Despite recent progress in the genetic characterization of congenital muscle diseases, the genes responsible for a significant proportion of cases remain unknown. We analysed two branches of a large consanguineous family in which four patients presented with a severe new phenotype, clinically marked by neonatal-onset muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies showed the unreported association of multi-minicores, caps and dystrophic lesions. Genome-wide linkage analysis followed by gene and exome sequencing in patients identified a homozygous nonsense mutation in TRIP4 encoding Activating Signal Cointegrator-1 (ASC-1), a poorly characterized transcription coactivator never associated with muscle or with human inherited disease. This mutation resulted in TRIP4 mRNA decay to around 10% of control levels and absence of detectable protein in patient cells. ASC-1 levels were higher in axial than in limb muscles in mouse, and increased during differentiation in C2C12 myogenic cells. Depletion of ASC-1 in cultured muscle cells from a patient and in Trip4 knocked-down C2C12 led to a significant reduction in myotube diameter ex vivo and in vitro, without changes in fusion index or markers of initial myogenic differentiation. This work reports the first TRIP4 mutation and defines a novel form of congenital muscle disease, expanding their histological, clinical and molecular spectrum. We establish the importance of ASC-1 in human skeletal muscle, identify transcriptional co-regulation as novel pathophysiological pathway, define ASC-1 as a regulator of late myogenic differentiation and suggest defects in myotube growth as a novel myopathic mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Cell Differentiation
  • Cell Line
  • Child
  • Codon, Nonsense*
  • Female
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Male
  • Mice
  • Muscle Development*
  • Muscle, Skeletal / metabolism
  • Muscular Diseases / congenital*
  • Muscular Diseases / genetics
  • Muscular Diseases / pathology*
  • Pedigree
  • RNA Stability
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Codon, Nonsense
  • TRIP4 protein, human
  • Transcription Factors