title: The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease.
abstract: 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.
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France, Inserm U787, Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, UPMC, UMR787, 75013 Paris, France.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Davignon
authors.affiliation: Inserm U787, Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, UPMC, UMR787, 75013 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Chauveau
authors.affiliation: Inserm U787, Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, UPMC, UMR787, 75013 Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Julien
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Dill
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duband-Goulet
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Cabet
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Buendia
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lilienbaum
authors.affiliation: Université Grenoble Alpes, Université Joseph Fourier, 38041 Grenoble, France, Biochimie Génétique et Moléculaire, CHRU de Grenoble, 38700 Grenoble, France, INSERM U386, Equipe Muscle et Pathologies, Grenoble Institut des Neurosciences, 38700 Grenoble, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: Pôle Neurosciences, Service de Neurologie, CHU de Rennes, 35033 Rennes, France.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Minot
authors.affiliation: CHU Angers, Service de génétique médicale, 49100 Angers, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Guichet
authors.affiliation: UPMC, Inserm UMRS974, CNRS FRE3617, Center for Research in Myology, 75013 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Allamand
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vadrot
authors.affiliation: Université Grenoble Alpes, Université Joseph Fourier, 38041 Grenoble, France, Biochimie Génétique et Moléculaire, CHRU de Grenoble, 38700 Grenoble, France, INSERM U386, Equipe Muscle et Pathologies, Grenoble Institut des Neurosciences, 38700 Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.affiliation: Pôle Neurosciences, Service de Neurologie, CHU de Rennes, 35033 Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Service de Pédiatrie, Centre Hospitalier de la Côte Basque, 64109 Bayonne, France.
authors.forename: Leïla
authors.initials: L
authors.lastname: Lazaro
authors.affiliation: Laboratoire d'Anatomo-Pathologie, CHU de Brest, 29609 Brest, France.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Leroy
authors.affiliation: Laboratoire d'Anatomo-Pathologie, CHU de Brest, 29609 Brest, France, EA 4685 Laboratoire de Neuroscience de Brest, Université Bretagne Occidentale, 29200 Brest, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
authors.affiliation: Inserm U787, Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, UPMC, UMR787, 75013 Paris, France, AP-HP, Laboratoire de Neuropathologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France and.
authors.forename: Odile
authors.initials: O
authors.lastname: Dubourg
authors.affiliation: Pathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptive Biology (BFA), University Paris Diderot, Sorbonne Paris Cité, BFA, UMR CNRS 8251, 75250 Paris Cedex 13, France, Inserm U787, Myology Group, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, UPMC, UMR787, 75013 Paris, France, AP-HP, Centre de Référence Maladies Neuromusculaires Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France ana.b.ferreiro@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
mesh_terms: D000293:Adolescent; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002648:Child; D018389:Codon, Nonsense; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D010375:Pedigree; D020871:RNA Stability; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; C459901:TRIP4 protein, human; D014157:Transcription Factors