Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

Abstract

Background: Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined.

Methods: We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis.

Results: We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S).

Conclusions: All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.

Figure 1 Diagrammatic representation of the alpha subunit of CACNA1S with S4 segments and arginine residues known to be mutated in hypokalemic periodic paralysis highlighted The novel arginine substitution reported here is boxed in gray. + indicates the number of positively charged residues in each S4 segment.

Figure 2 Diagrammatic representation of the alpha subunit of SCN4A with S4 segments and arginine residues known to be mutated highlighted Novel arginine mutations reported here are boxed in gray. + indicates the number of positively charged residues in each S4 segment. *Note substitutions of R1448 cause a phenotype of paramyotonia congenita.