Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation.
The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.
Grant
Augustus O
AO
Duke University Medical Center, Box 3504, Durham, North Carolina 27710, USA. grant007@mc.duke.edu
Carboni
Michael P
MP
Neplioueva
Valentina
V
Starmer
C Frank
CF
Memmi
Mirella
M
Napolitano
Carlo
C
Priori
Silvia
S
D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
D011994:Recombinant Proteins; D015222:Sodium Channels