Certain forms of myotonia, a condition characterized by delayed relaxation of 
muscle secondary to sarcolemmal hyperexcitability, are caused by diminished 
chloride conductance in the muscle cell membrane. We have investigated the 
molecular basis for decreased muscle chloride conductance in the myotonic goat, 
an historically important animal model for the elucidation of the role of 
chloride in muscle excitation. A single nucleotide change causing the 
substitution of proline for a conserved alanine residue in the carboxyl terminus 
of the goat muscle chloride channel (gCIC-1) was discovered. Heterologous 
expression of the mutation demonstrated a substantial (+47 mV) shift in the 
midpoint of steady-state activation of the channel, resulting in a diminished 
channel open probability at voltages near the resting membrane potential of 
skeletal muscle. These results provide a molecular basis for the decreased 
chloride conductance in myotonic muscle.