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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are revealed in human myotubes

¹Centre Hospitalier Universitaire of Nice, Centre de Référence Maladies Neuromusculaires et Sclérose Latérale Amyotrophique, Institut National de la Santé et de la Recherche Médicale Unité 638, Institut Fédératif de Recherche 50, Nice; ²University of Nice Sophia Antipolis, Transport Ionique Aspects Normaux et Pathologiques, Formation de Recherche en Evolution 3093 Centre National de la Recherche Scientifique, Parc Valrose, Nice; ³Centre Hospitalier Universitaire of Caen, Service de Neurologie et Laboratoire de Neuropathologie, Caen; ⁴University of Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097 Centre National de la Recherche Scientifique, Sophia Antipolis, Valbonne; ⁵Centre de Référence des Canalopathies Musculaires, Fédération des Maladies du Système Nerveux; Université Pierre et Marie Curie, Unité Mixte de Recherche S546; Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 546, Paris; and ⁶Biochemistry and Genetics, Hôpital Pitié-Salpêtrière, Assistance Publique, Hôpitaux de Paris, and Unité Mixte de Recherche 546, Université Pierre et Marie Curie and Institut National de la Santé et de la Recherche Médicale, Paris, France

Submitted 10 October 2008 ; accepted in final form 25 June 2009

Andersen's syndrome is a rare disorder that has been defined with a triad: periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle weakness has been reported in two-thirds of the patients. KCNJ2 remains the only gene linked to Andersen's syndrome; this gene encodes for the -subunit of the strong inward-rectifier K⁺ channel Kir2.1. Several studies have shown that Andersen's syndrome mutations lead to a loss of function of the K⁺ channel activity in vitro. However, ex vivo studies on isolated patient muscle tissue have not been reported. We have performed muscle biopsies of controls and patients presenting with clinically and genetically defined Andersen's syndrome disorder. Myoblasts were cultured and characterized morphologically and functionally using the whole cell patch-clamp technique. No morphological difference was observed between Andersen's syndrome and control myoblasts at each passage of the cell culture. Cellular proliferation and viability were quantified in parallel with direct cell counts and showed no difference between control and Andersen's syndrome patients. Moreover, our data show no significant difference in myoblast fusion index among Andersen's syndrome and control patients. Current recordings carried out on myotubes revealed the absence of an inwardly rectifying Ba²⁺-sensitive current in affected patient cells. One consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift of the resting membrane potential toward depolarizing potentials. Our data describe for the first time the functional consequences of Andersen's syndrome mutations ex vivo and provide clues to the K⁺ channel pathophysiology in skeletal muscle.

skeletal muscle; Andersen's syndrome; potassium ion channels