Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor

Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in CACNA1S coding for Ca(V)1.1 and SCN4A coding for Na(V)1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either Ca(V)1.1 or Na(V)1.4. Mutant channels have aberrant leak currents called 'gating pore currents', and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five hypokalaemic periodic paralysis cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other hypokalaemic periodic paralysis families. One case is R219K in Na(V)1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in Ca(V)1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of Ca(V)1.1-R897K. Na(V)1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by Na(V)1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical hypokalaemic periodic paralysis phenotypes do not fit the canonical view that the essential defect in hypokalaemic periodic paralysis mutant channels is the gating pore current and raise the possibility that hypokalaemic periodic paralysis pathogenesis might be heterogeneous and diverse.