Patch clamp studies of the thr1313met mutant sodium channel causing paramyotonia congenita

Paramyotonia congenita (PC) is an autosomal-dominant disorder due to a poin t mutation in the adult skeletal muscle Na channel gene. Muscle fibers from PC patients have normal membrane properties at 32 degreesC. At 27 degreesC , they are inexcitable, have increased Na conductance, and have a reduced r esting membrane potential of -40 mV, To define the biophysical basis for th e muscle membrane abnormalities, we performed patch clamp whole-cell and ou tside-out single Na channel studies at 22 degreesC on cultured human muscle cells from 4 control patients and 2 sisters with PC and the thr1313met mut ant Na channel. The whole-cell studies showed no difference in window curre nts. Unlike cells transfected with the thr1313met mutant Na channel, the in activation time constant, tau (h), for PC cells was similar to control cell s. For PC recordings containing long-duration single Na channel openings, m ean open time was prolonged at -60, -40, and -20 mV. The long-duration Na c hannel openings occurred randomly with no evidence of modal gating, The num ber of channel openings, occurrence of late openings, and the prolonged mea n open time resulted in a sustained inward Na current at -40 mV. We suggest that the biophysical marker of the thr1313met mutant Na channel is a volta ge- and temperature-dependent abnormality in mutant single Na channel behav ior. (C) 2000 John Wiley & Sons, Inc.