Neurology 2002;58:1266-1272
© 2002 American Academy of Neurology
Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5
S. Bendahhou, PhD,
T. R. Cummins, PhD,
R. W. Kula, MD,
Y.-H. Fu, PhD and
L. J. Ptácek, MD
From the Howard Hughes Medical Institute (Drs. Bendahhou and Ptácek), Department of Neurobiology and Anatomy (Dr. Fu), Eccles Institute of Human Genetics, University of Utah, Salt Lake City; Department of Neurology and Human Genetics (Dr. Ptácek), Department of Neurology (Dr. Cummins), Yale University School of Medicine, New Haven, and Neuroscience Research Center (Dr. Cummins), VA Medical Center, West Haven, CT; and Department of Neurology (Dr. Kula), State University of New York Health Science Center at Brooklyn, The Long Island College Hospital, New York.
Address correspondence and reprint requests to Dr. S. Bendahhou, Howard Hughes Medical Institute, Eccles Institute of Human Genetics University of Utah, Building 533, Room 4425, Salt Lake City, UT 84112; e-mail: said{at}howard.genetics.utah.edu
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.
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