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: 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 Cortese, Roger Cox, Steve D M Brown, Valter Tucci, Henning Wackerhage, Anthony A Amato, Linda Greensmith, Martin Koltzenburg, Michael G Hanna, Abraham Acevedo-Arozena
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 12 Pg. 3171-85 (Dec 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 25348630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Chemical References

• NAV1.4 Voltage-Gated Sodium Channel
• SCN4A protein, human
• Scn4a protein, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics)
• Animals
• Channelopathies (genetics)
• Humans
• Mice
• Mutation (genetics)
• Myotonia (genetics)
• Myotonic Disorders (genetics)
• NAV1.4 Voltage-Gated Sodium Channel (genetics)
• Paralyses, Familial Periodic (genetics)
• Pedigree