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


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.

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This work was supported by the Centre National de la Recherche Scientifique (CNRS) and Association Française contre les Myopathies (AFM) grant (S.B.) and Chateaubriand fellowships (D.S.) and City of Nice fellowship (S.G. and A.V.). We thank the Vector Core of the University Hospital of Nantes for providing the adenovirus vectors.

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The authors declare having no conflict of interest.

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Correspondence to Saïd Bendahhou.

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Simkin, D., Robin, G., Giuliano, S. et al. Andersen’s syndrome mutants produce a knockdown of inwardly rectifying K+ channel in mouse skeletal muscle in vivo. Cell Tissue Res 371, 309–323 (2018). https://doi.org/10.1007/s00441-017-2696-7

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