Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes

Citation
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
Citations number
38
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
33
Year of publication
2001
Pages
30623 - 30630
Database
ISI
SICI code
0021-9258(20010817)276:33<30623:IBALQS>2.0.ZU;2-U
Abstract
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.