Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na⁺ channel

Abstract

Aim: We compared the clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in domain II (S5-S6) of human, hNa v 1.5, cardiac Na + channels.Methods: Full clinical evaluation of pedigree members through three generations of a Chinese family combined with SCN5A sequencing from genomic DNA was compared with patch and voltage-clamp results from two independent expression systems.Results: The four mutation carriers showed bradycardia, and slowed sinoatrial, atrioventricular and intraventricular conduction. Two also showed sick sinus syndrome; two had ST elevation in leads V1 and V2. Unlike WT-hNa v 1.5, whole-cell patch-clamped HEK293 cells expressing R878C-hNa v 1.5 showed no detectable Na + currents (i Na ), even with substitution of a similarly charged lysine residue. Voltage-clamped Xenopus oocytes injected with either 0.04 or 1.5 lg lL )1 R878C-hNa v 1.5 cRNA similarly showed no i Na , yet WT-hNa v 1.5 cRNA diluted to 0.0004-0.0008 ng lL )1 resulted in expression of detectable i Na . i Na was simply determined by the amount of injected WT-hNa v 1.5: doubling the dose of WT-hNa v 1.5 cRNA doubled i Na . i Na amplitudes and activation and inactivation characteristics were similar irrespective of whether WT-hNa v 1.5 cRNA was given alone or combined with equal doses of R878C-hNa v 1.5 cRNA therefore excluding dominant negative phenotypic effects. Na + channel function in HEK293 cells transfected with R878C-hNa v 1.5 was not restored by exposure to mexiletine (200 lm) and lidocaine (100 lm). Fluorescence confocal microscopy using E3-Nav1.5 antibody demonstrated persistent membrane expression of both WT and R878C-hNa v 1.5. Modelling studies confirmed that such i Na reductions reproduced the SSS phenotype. Conclusion: Clinical consequences of the novel R878C mutation correlate with results of physiological studies.

Characterization of N-terminally mutated cardiac Na+ channels associated with long QT syndrome 3 and Brugada syndrome

“…Such defects are believed to result in an action potential widening and consequently, in the observed QT prolongation. In BrS or CCD, mutant channels often show loss-of-function features, like reduced channel availability at the resting membrane potential (Rivolta et al, 2001), a positive shift of steady-state activation (Vatta et al, 2002a; Potet et al, 2003), impaired trafficking to the plasma membrane (Baroudi et al, 2001; Valdivia et al, 2004), or the inability to conduct Na + (Kyndt et al, 2001; Zhang et al, 2008). Such defects can explain cardiac conduction abnormalities and the observed ST segment elevation (Alings and Wilde, 1999; Yan and Antzelevitch, 1999).…”

Diagnostic’s experience and ten-year tretment outcomes of patients with brugada syndrome

“…Сегодня накоплено достаточ-ное количество данных о мутациях в гене SCN5A, реализующихся по типу loss of function и способных привести к смешению, перекры-тию фенотипов, что обусловливает одновремен-ное появление у пациента фенотипических про-явлений синдрома Бругада и нарушений прово-димости и/или СССУ [23]. Известны мутации Y1495X, R878C и E161K, проявляющиеся про-грессирующим нарушением проводимости и ти-пичными изменениями на ЭКГ в виде элевации сегмента ST в правых грудных отведениях [17,24,25]. Описана мутация R367H в гене SCN5A у пациента с синдромом Бругада и СССУ [26].…”

Brugada syndrome and cardiac sodium channelopathy overlap syndromes: different faces of SCN5A mutations

“…Выполнена смена ЭКС на имплантируемый КД, который произвел один мотивированный шок за 2 года наблюдения. Генотипирование выявило известную высококонсервативную замену R878C в порообразующей области DII-S5/S6, ранее описанную в связи с синдромом Бругада, дефектами проводимости и СССУ [20,24]. У пробанда (49 лет, женщина) с пароксиз-мальной ФП, предсердно-желудочковыми нару-шениями проводимости на ЭКГ (P-Q 238 мс во II отведении, P-Q 258 мс в отведении V2, QRS 135 мс во II отведении) и ранее имплантирован-ным ЭКС для лечения синусовой брадикардии выявлен Бругада-паттерн II типа.…”