Hypokalemic Periodic Paralysis Cases with Substitutions from Arginine to Lysine in the Voltage Sensor

Abstract

Familial hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle disease caused by the dysregulation of excitability in salcolemma. HypoPP is characterized by repeated episodic paralytic attacks with hypokalemia and several mutations in CACNA1S gene coding Cav1.1 and SCN4A gene coding Nav1.4 have been identified as causative mutations. Most of the mutations are substitution to non-charged amino acid from the positively charged arginine (R) in segment 4 (S4) of the voltage sensor in either Cav1.1 or Nav1.4. Biophysical experiments demonstrated that the loss of the charge in S4 by the arginine-to-non-charged substitution creates a leak current called “gating pore current”. Since the discovery, “the gating pore current theory” has been suggested as the common pathogenic feature in HypoPP. However, the pathological mechanism from generation of “gating pore current” to paralytic attack is still unknown. In this report, we have identified five cases with an arginine(R)-to-lysine (K) substitution in voltage sensor, which retained positive net charge of S4 ; one is a Japanese boy with R219K mutation in SCN4A gene and the other four are one Japanese man, one French man and two French brothers with R897K mutation in CACNA1S gene. All cases presented typical paralytic episodes with hypokalemia and, in four of five cases, significant decrement in the compound action potential was observed with prolonged exercise test. From Nav1.4-R219K mutant channel expressed in vitro, we measured the ionic current by patch-clamp technique and the gating pore current by cut-open voltage clamp technique. Nav1.4-R219K revealed gating pore current, but the size of the conductance was smaller compared to that observed in other mutant HypoPP-Nav1.4 channels previously reported. Our data might provide a new insight in pathogenic mechanism of HypoPP.