Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Silvia Corrochano, Roope Männikkö, Peter I Joyce, Philip McGoldrick, Jessica Wettstein, Glenda Lassi, Dipa L Raja Rayan, Gonzalo Blanco, Colin Quinn, Andrianos Liavas, Arimantas Lionikas, Neta Amior, James Dick, Estelle G Healy, Michelle Stewart, Sarah Carter, Marie Hutchinson, Liz Bentley, Pietro Fratta, Andrea CorteseRoger Cox, Steve D M Brown, Valter Tucci, Henning Wackerhage, Anthony A Amato, Linda Greensmith, Martin Koltzenburg, Michael G Hanna, Abraham Acevedo-Arozena

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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.

Original languageEnglish
Pages (from-to)3171-3185
Number of pages15
JournalBrain
Volume137
Issue number12
DOIs
Publication statusPublished - Dec 2014

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Keywords

  • SCN4A
  • mice
  • AMPK
  • periodic paralysis
  • myotonia

Cite this

Corrochano, S., Männikkö, R., Joyce, P. I., McGoldrick, P., Wettstein, J., Lassi, G., ... Acevedo-Arozena, A. (2014). Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis. Brain, 137(12), 3171-3185. https://doi.org/10.1093/brain/awu292