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From the Departments of Applied Physiology (S. Wagner and Drs. Lerche, Mitrovic, Heine, and Lehmann-Horn) and Neurology (Drs. Lerche and Mitrovic), University of Ulm, Ulm, Germany; and the Department of Medicine and Pharmacology (Dr. George), Vanderbilt University Medical Center, Nashville, TN.
Address correspondence and reprint requests to Dr. Frank Lehmann-Horn, Abteilung Angewandte Physiologie, Universität Ulm, D-89069 Ulm, Germany.
A point mutation A4078G predicting the amino acid exchange Met1360Val in segment IV/S1 of the human muscle sodium channel 
-subunit was identified in a family presenting features of hyperkalemic periodic paralysis and paramyotonia congenita with sex-related modification of expression. In this family, only one male member is clinically affected, presenting episodes of flaccid weakness as well as paradoxical myotonia and cold-induced weakness. Three female family members who have the same mutation show only myotonic bursts on EMG. We studied the functional defect caused by this mutation by investigating recombinant wild type (WT) and mutant sodium channels expressed in a mammalian cell line (HEK293) using the patch-clamp technique. With mutant channels, the decay of the sodium currents was two times slower than with WT, the steady-state inactivation curve was shifted by-13 mV, and recovery from inactivation was 1.5 times faster. High extracellular potassium (9 mM) did not affect channel gating. Single-channel measurements revealed prolonged mean open times and an increased number of reopenings. The results are remarkable with respect to the lack of complete penetrance usually seen with sodium channelopathies and the site of mutation that was formerly not thought to be involved in channel inactivation.
Supported by the Deutsche Forschungsgemeinschaft (Le 481/3-3), the Deutsche Gesellschaft für Muskelkranke, the Muscular Dystrophy Association, and NIH Grant N532387(ALG).
Received February 21, 1997. Accepted in final form April 21, 1997.
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