title: Functional Characterization of a Central Core Disease RyR1 Mutation (p.Y4864H) Associated with Quantitative Defect in RyR1 Protein.
abstract: BACKGROUND
  Central Core Disease (CCD) is a congenital myopathy often resulting from a mutation in RYR1 gene. Mutations in RyR1 can increase or decrease channel activity, or induce a reduction in the amount of protein. The consequences of a single mutation are sometimes multiple and the analysis of the functional effects is complex.
  
  
  OBJECTIVE
  The consequences of the p.Y4864H mutation identified in a CCD patient have been studied regarding both RyR1 function and amount.
  
  
  METHODS
  The amount of RyR1 in human and mouse muscles was evaluated using qRT-PCR and quantitative Western blot, and calcium release was studied using calcium imaging on primary cultures. The results were compared between human and mouse.
  
  
  RESULTS
  The p.Y4864H mutation induced an alteration of calcium release, and in addition was associated to a reduction in the amount of RyR1 in the patient's muscle. This suggests two possible pathophysiological mechanisms: the alteration of calcium release could result from a modification of the channel properties of RyR1 or from a RyR1 reduction. In order to discriminate between the two hypotheses, we used the heterozygous RyR1 knockout (RyR1+/-) mouse model showing a comparable RyR1 protein reduction. No reduction in calcium release was observed in primary muscle culture from these mice, and no muscle weakness was measured.
  
  
  CONCLUSIONS
  Because the reduction in the amount of RyR1 protein has no functional consequences in the murine model, the muscle weakness observed in the patient is most likely the result of a modification of the calcium channel function of RyR1 due to the p.Y4864H mutation.
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Cacheux
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Blum
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Sébastien
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Wozny
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Brocard
authors.affiliation: UMRS974 Inserm, UMR7215 CNRS, Institut de Myologie, GH PitiéSalpétrière, 47 bd de l'hôpital, Paris, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.affiliation: UMRS974 Inserm, UMR7215 CNRS, Institut de Myologie, GH PitiéSalpétrière, 47 bd de l'hôpital, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roux-Buisson
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.affiliation: Département Anesthésie-Réanimation, Hôpital Roger Salengro, CHRU de Lille, Lille, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Krivosic
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, Davis CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Allen
authors.affiliation: Service de Neurologie, Hôpital Roger Salengro, CHRU de Lille, Lille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacour
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Hôpital Michallon, Biochimie Génétique et Moléculaire, Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marty
keywords: Central Core Disease; Malignant Hyperthermia; Ryanodine receptor; calcium release