Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5.
BACKGROUND
Mutations in the human skeletal muscle sodium channels are associated with hyperKPP, hypoKPP, paramyotonia congenita, and potassium-aggravated myotonia. This article describes the clinical manifestations of a patient with hyperKPP carrying a mutation (L689I) occurring in the linker DIIS4-S5 and its functional expression in a mammalian system.


OBJECTIVE
To correlate the clinical manifestations of hyperkalemic periodic paralysis (hyperKPP) with the functional expression of a sodium channel mutation.


METHODS
The mutation was introduced into a mammalian expression vector and expressed in the human embryonic kidney 293 cells. The functional expression of the L689I and that of the wild-type channels was monitored using the whole cell voltage-clamp technique.


RESULTS
There was no change in the kinetics of fast inactivation, and inactivation curves were indistinguishable from that of wild-type channels. However, the L689I mutation caused a hyperpolarizing shift in the voltage dependence of activation and the mutant channels showed an impaired slow inactivation process. In addition, the mutant channels have a larger persistent current at -40 mV where window current may occur.


CONCLUSIONS
The L689I mutation has similar effects to the T704M mutation and causes hyperKPP in this family. Because both of these hyperKPP mutations cause episodic muscle weakness, and because patients harboring another mutation (I693T) also can have episodic weakness, it is hypothesized that mutations occurring in this region of the sodium channel may cause episodic weakness through an impaired slow inactivation process coupled with enhanced activation.
Bendahhou
S
S
Howard Hughes Medical Institute, Eccles Institute of Human Genetics, University of Utah, Salt Lake City 84112, USA. said@howard.genetics.utah.edu
Cummins
T R
TR
Kula
R W
RW
Fu
Y-H
YH
Ptácek
L J
LJ
D000328:Adult; D019943:Amino Acid Substitution; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004594:Electrophysiology; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000503:physiopathology*; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics; D010243:Paralysis / Q000235:genetics* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
D015222:Sodium Channels; D004247:DNA