Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia.
BACKGROUND
Missense mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. The mechanistic basis for the phenotypic variability of these allelic disorders of muscle excitability remains unknown. An atypical phenotype with cold-induced hypokalemic paralysis and myotonia at warm temperatures was reported to segregate with the P1158S mutation.


OBJECTIVE
This study extends the functional characterization of the P1158S mutation and tests the specific hypothesis that impairment of Na channel slow inactivation is a common feature of periodic paralysis.


METHODS
Mutant NaV1.4 channels (P1158S) were transiently expressed in human embryonic kidney cells and characterized by voltage-clamp studies of Na currents.


RESULTS
Wild-type and P1158S channels displayed comparable behavior at 37 degrees C, but upon cooling to 25 degrees C, mutant channels activated at more negative potentials and slow inactivation was destabilized.


CONCLUSIONS
Consistent with other NaV1.4 mutations associated with a paralytic phenotype, the P1158S mutation disrupts slow inactivation. The unique temperature sensitivity of the channel defect may contribute to the unusual clinical phenotype.
Webb
Jadon
J
Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8813, USA.
Cannon
Stephen C
SC
D000200:Action Potentials / Q000235:genetics; D001831:Body Temperature / Q000235:genetics; D002460:Cell Line; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003080:Cold Temperature / Q000009:adverse effects; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D009119:Muscle Contraction / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D020967:Myotonic Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D020513:Paralysis, Hyperkalemic Periodic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011930:Reaction Time / Q000235:genetics; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels