multiple loss-of-function mechanisms contribute to scn5a-related familial sick sinus syndrome多个功能丧失机制有助于scn5a-related家族病窦综合征.pdfVIP

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multiple loss-of-function mechanisms contribute to scn5a-related familial sick sinus syndrome多个功能丧失机制有助于scn5a-related家族病窦综合征.pdf

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multiple loss-of-function mechanisms contribute to scn5a-related familial sick sinus syndrome多个功能丧失机制有助于scn5a-related家族病窦综合征

Multiple Loss-of-Function Mechanisms Contribute to SCN5A-Related Familial Sick Sinus Syndrome 1. 1. 1 1 2 1 Junhong Gui , Tao Wang , Richard P. O. Jones , Dorothy Trump , Thomas Zimmer *, Ming Lei * 1 Cardiovascular and Genetic Medicine Research Groups, School of Biomedicine, University of Manchester, Manchester, United Kingdom, 2 Institute of Physiology II, Friedrich Schiller University, Jena, Germany 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 1.5 (hNa 1.5) mutant channels previously linked to this disease. v v Methodology/Principal Findings: Mutant hNa 1.5 channels expressed by HEK293 cells and Xenopus oocytes were v 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 hNav 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 redu