Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome.
PLoS One
; 5(6): e10985, 2010 Jun 07.
Article
em En
| MEDLINE
| ID: mdl-20539757
ABSTRACT
BACKGROUND:
To identify molecular mechanisms underlying SCN5A-related sick sinus syndrome (SSS), a rare type of SSS, in parallel experiments we elucidated the electrophysiological properties and the cell surface localization of thirteen human Na(v)1.5 (hNa(v)1.5) mutant channels previously linked to this disease. METHODOLOGY/PRINCIPALFINDINGS:
Mutant hNa(v)1.5 channels expressed by HEK293 cells and Xenopus oocytes were investigated by whole-cell patch clamp and two-microelectrode voltage clamp, respectively. HEK293 cell surface biotinylation experiments quantified the fraction of correctly targeted channel proteins. Our data suggested three distinct mutant channel subtypes Group 1 mutants (L212P, P1298L, DelF1617, R1632H) gave peak current densities and cell surface targeting indistinguishable from wild-type hNa(v)1.5. Loss-of-function of these mutants resulted from altered channel kinetics, including a negative shift of steady-state inactivation and a reduced voltage dependency of open-state inactivation. Group 2 mutants (E161K, T220I, D1275N) gave significantly reduced whole-cell currents due to impaired cell surface localization (D1275N), altered channel properties at unchanged cell surface localization (T220I), or a combination of both (E161K). Group 3 mutant channels were non-functional, due to an almost complete lack of protein at the plasma membrane (T187I, W1421X, K1578fs/52, R1623X) or a probable gating/permeation defect with normal surface localisation (R878C, G1408R). CONCLUSIONS/SIGNIFICANCE:
This study indicates that multiple molecular mechanisms, including gating abnormalities, trafficking defects, or a combination of both, are responsible for SCN5A-related familial SSS.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Síndrome do Nó Sinusal
/
Canais de Sódio
/
Proteínas Musculares
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article