Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy

PLoS Genet. 2013 Jun;9(6):e1003550. doi: 10.1371/journal.pgen.1003550. Epub 2013 Jun 13.


Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Humans
  • Mice
  • Muscle Development / genetics*
  • Muscles / metabolism
  • Muscles / physiopathology*
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Muscular Dystrophy, Facioscapulohumeral / pathology
  • Myoblasts / metabolism
  • Myoblasts / pathology
  • Oligonucleotide Array Sequence Analysis
  • Organ Specificity


  • Cadherins
  • FAT1 protein, human

Grants and funding

The work in F. Helmbacher's laboratory was supported by the Centre National de la recherche scientifique (CNRS), through an Action thématique et incitative sur le programme (ATIP) start-up grant, by grants from the Fondation pour la recherche médicale (FRM, starting grant and FRM Equipe 2007), from the Association Française contre les myopathies (AFM-Téléthon), from the Fondation pour la recherche sur le cerveau (FRC), from the Agence Nationale pour la Recherche (ANR Neuro 2007), the Association pour la recherche contre le cancer (ARC), Fondation de France, and from the FSHD global organisation. Work in N. Levy's Laboratory was supported by the CNRS, by the Institut National de la Santé et la Recherche Médicale (INSERM), by the Aix-Marseille Université, by the AFM-Telethon through the strategic pole MNH-Decrypt to N. Levy, and through a grant by FSHD global organization to F. Helmbacher. F. Puppo was supported by a fellowship from the AFM, S. Roche, was supported through an ANR grant to F. Magdinier. The contribution of the Region Provence Alpes Côtes d'Azur and of the Aix-Marseille Université to the IBDM animal and imaging facilities is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.