I. Rivolta et al., Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes, J BIOL CHEM, 276(33), 2001, pp. 30623-30630
Defects of the SCN5A gene encoding the cardiac sodium channel a-subunit are
associated with both the long,QT-3 (LQT-3) subtype of long-QT syndrome and
Brugada syndrome (BrS). One previously described SCN5A mutation (1795insD)
in the C terminus results in a clinical phenotype combining QT prolongatio
n and ST segment elevation, indicating a close interrelationship between th
e two disorders. Here we provide additional evidence that these two disorde
rs are closely related. We report the analysis of two novel mutations on th
e same codon, Y1795C (LQT-3) and Y1795H (BrS), expressed in HEK 293 cells a
nd characterized using whole-cell patch clamp procedures. We find marked an
d opposing effects on channel gating consistent with activity associated wi
th the cellular basis of each clinical disorder. Y1795H speeds and Y1795C s
lows the onset of inactivation. The Y1795H, but not the Y1795C, mutation ca
uses a marked negative shift in the voltage dependence of inactivation, and
neither mutation affects the kinetics of the recovery from inactivation. I
nterestingly, both mutations increase the expression of sustained Na+ chann
el activity compared with wild type (WT) channels, although this effect is
most pronounced for the Y1795C mutation, and both mutations promote entranc
e into an intermediate or a slowly developing inactivated state. These data
confirm the key role of the C-terminal tail of the cardiac Na+ channel in
the control of channel gating, illustrate how subtle changes in channel bio
physics can have significant and distinct effects in human disease, and, ad
ditionally, provide further evidence of the close interrelationship between
BrS and LQT-3 at the molecular level.