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

TY - JOUR

T1 - Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

AU - Corrochano, Silvia

AU - Männikkö, Roope

AU - Joyce, Peter I.

AU - McGoldrick, Philip

AU - Wettstein, Jessica

AU - Lassi, Glenda

AU - Rayan, Dipa L Raja

AU - Blanco, Gonzalo

AU - Quinn, Colin

AU - Liavas, Andrianos

AU - Lionikas, Arimantas

AU - Amior, Neta

AU - Dick, James

AU - Healy, Estelle G.

AU - Stewart, Michelle

AU - Carter, Sarah

AU - Hutchinson, Marie

AU - Bentley, Liz

AU - Fratta, Pietro

AU - Cortese, Andrea

AU - Cox, Roger

AU - Brown, Steve D. M.

AU - Tucci, Valter

AU - Wackerhage, Henning

AU - Amato, Anthony A.

AU - Greensmith, Linda

AU - Koltzenburg, Martin

AU - Hanna, Michael G.

AU - Acevedo-Arozena, Abraham

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - AMPK

KW - Mice

KW - Myotonia

KW - Periodic paralysis

KW - SCN4A

UR - http://www.scopus.com/inward/record.url?scp=84922359133&partnerID=8YFLogxK

U2 - 10.1093/brain/awu292

DO - 10.1093/brain/awu292

M3 - Article

AN - SCOPUS:84922359133

SN - 0006-8950

VL - 137

SP - 3171

EP - 3185

JO - Brain

JF - Brain

IS - 12

ER -