title: Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis.
abstract: Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Corrochano
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Roope
authors.initials: R
authors.lastname: Männikkö
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Joyce
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: McGoldrick
authors.affiliation: 3 University of Aberdeen, Institute of Medical Sciences, Scotland, UK a.acevedo@har.mrc.ac.uk.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wettstein
authors.affiliation: 4 Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Glenda
authors.initials: G
authors.lastname: Lassi
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Dipa L
authors.initials: DL
authors.lastname: Raja Rayan
authors.affiliation: 5 Biology Department, University of York, York, UK.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Blanco
authors.affiliation: 6 Brigham and Women's Hospital, Harvard Medical School, Boston, US.
authors.forename: Colin
authors.initials: C
authors.lastname: Quinn
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Andrianos
authors.initials: A
authors.lastname: Liavas
authors.affiliation: 3 University of Aberdeen, Institute of Medical Sciences, Scotland, UK.
authors.forename: Arimantas
authors.initials: A
authors.lastname: Lionikas
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Neta
authors.initials: N
authors.lastname: Amior
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Dick
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Estelle G
authors.initials: EG
authors.lastname: Healy
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stewart
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Carter
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Hutchinson
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Liz
authors.initials: L
authors.lastname: Bentley
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: 7 Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cortese
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Cox
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.affiliation: 4 Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.affiliation: 3 University of Aberdeen, Institute of Medical Sciences, Scotland, UK.
authors.forename: Henning
authors.initials: H
authors.lastname: Wackerhage
authors.affiliation: 6 Brigham and Women's Hospital, Harvard Medical School, Boston, US.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Koltzenburg
authors.affiliation: 2 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: 1 MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000818:Animals; D053447:Channelopathies / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009222:Myotonia / Q000235:genetics*; D020967:Myotonic Disorders / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D010245:Paralyses, Familial Periodic / Q000235:genetics*; D010375:Pedigree
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; C491391:Scn4a protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMPK; SCN4A; mice; myotonia; periodic paralysis