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Cell Tissue Res. 2018 Feb;371(2):309-323. doi: 10.1007/s00441-017-2696-7. Epub 2017 Oct 10.

Andersen's syndrome mutants produce a knockdown of inwardly rectifying K+ channel in mouse skeletal muscle in vivo.

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UMR 7370 CNRS, LP2M, Laboratoire d'Excellence - ICST, Université Côte d'Azur, Faculté de Médecine, 06107, Nice, France.
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
UMR CNRS 5534, Université Claude Bernard Lyon 1, 69622, Lyon, France.
Institute for Molecular Health Science, ETH Zurich, 8093, Zurich, Switzerland.
Service de Cardiologie, Pasteur Hospital, CHU de Nice, 06107, Nice, France.
UMR 7275 CNRS, IPMC, Université Côte d'Azur, 06560, Valbonne, France.
UMR 7284 CNRS, INSERM, IBV, Université Côte d'Azur, Faculté de Médecine, 06107, Nice, France.
INSERM U1046, UMR CNRS 9214, Université de Montpellier, CHRU de Montpellier, 34295, Montpellier, France.
UMR 7370 CNRS, LP2M, Laboratoire d'Excellence - ICST, Université Côte d'Azur, Faculté de Médecine, 06107, Nice, France.


Andersen's syndrome (AS) is a rare autosomal disorder that has been defined by the triad of periodic paralysis, cardiac arrhythmia, and developmental anomalies. AS has been directly linked to over 40 different autosomal dominant negative loss-of-function mutations in the KCNJ2 gene, encoding for the tetrameric strong inward rectifying K+ channel KIR2.1. While KIR2.1 channels have been suggested to contribute to setting the resting membrane potential (RMP) and to control the duration of the action potential (AP) in skeletal and cardiac muscle, the mechanism by which AS mutations produce such complex pathophysiological symptoms is poorly understood. Thus, we use an adenoviral transduction strategy to study in vivo subcellular distribution of wild-type (WT) and AS-associated mutant KIR2.1 channels in mouse skeletal muscle. We determined that WT and D71V AS mutant KIR2.1 channels are localized to the sarcolemma and the transverse tubules (T-tubules) of skeletal muscle fibers, while the ∆314-315 AS KIR2.1 mutation prevents proper trafficking of the homo- or hetero-meric channel complexes. Whole-cell voltage-clamp recordings in individual skeletal muscle fibers confirmed the reduction of inwardly rectifying K+ current (IK1) after transduction with ∆314-315 KIR2.1 as compared to WT channels. Analysis of skeletal muscle function revealed reduced force generation during isometric contraction as well as reduced resistance to muscle fatigue in extensor digitorum longus muscles transduced with AS mutant KIR2.1. Together, these results suggest that KIR2.1 channels may be involved in the excitation-contraction coupling process required for proper skeletal muscle function. Our findings provide clues to mechanisms associated with periodic paralysis in AS.


Adenovirus; Andersen’s syndrome; Channelopathies; KIR2.1; Skeletal muscle

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