Targeted mutation of NaV1.4 causes paralysis in mouse as observed in attacks of Hyperkalemic Periodic Paralysis (HyperKPP)

Abstract

The single point mutation M1592V on the skeletal muscle sodium channel, NaV1.4, causes human HyperKPP. For this specific point mutation, the onset of the paralytic attacks occurs between 5–10 years of age. In response to several known triggers, such attacks may then increase in frequency, duration and intensity until adolescence, but typically they diminish in mid‐ adulthood. By that time, fixed muscle weakness and a major shift toward type I and IIA fibers are observed in many muscles. The objective of this study was to determine if introducing a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene (mice(+/M1592V)) encoding the skeletal muscle voltage‐gated Na+ channel NaV1.4 also may predispose to paralytic attacks with changes in frequency and intensity. Paralysis of the hindlimb muscles were observed during the period of 6‐12 weeks postnatal. By 8 weeks of age, EDL muscle from mice(+/M1592V) had more than 2‐fold less type IIB and 2‐times more type IIA fibers when compared to EDL muscles of wild type mice. Finally, measurement of NaV1.4 content by immunohistochemistry showed a small decrease in protein content from 3 to 8 weeks of age followed by no further changes up to 16 weeks of age. More importantly, there was no difference in NaV1.4 protein content between wild type and mice(+/M1592V). We conclude that altered mouse NaV1.4 equivalent to the human M1592V mutation causes paralytic attacks during a postnatal window of 6–12 weeks and a shift toward type IIA fibers that is not associated with a change in NaV1.4 protein content.