Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine

American Journal of Physiology. Heart and Circulatory Physiology
Bi-Hua TanJonathan C Makielski

Abstract

Mutations in the cardiac Na(+) channel gene SCN5A cause loss of function and underlie arrhythmia syndromes. SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss of function and rescue for G1406R, a mutation reported to cause Brugada syndrome. Mutant and wild-type (WT) channels in both backgrounds were transfected into HEK-293 cells and incubated for up to 72 h with and without mexiletine. At 8 h, neither current nor cell surface expression was observed for the mutant in either background, but both were present in WT channels. At 24 h, small (<10% compared with WT) currents were noted and accompanied by cell surface expression. At 48 h, current density was approximately 40% of WT channels for the mutant in the Q1077del variant background but remained at <10% of WT channels in Q1077. Current levels were stable by 72 h. Coexpression with beta(1)- or beta(3)-subunits or insertion of the polymorphism H558R in the background did not significantly affect current expression. Mexiletine restored current density of the mutant channel in both backgrounds to nearly WT levels. The mutant channels also showed a ne...Continue Reading

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Citations

Dec 3, 2009·Journal of Molecular Neuroscience : MN·Jana SchirmeyerStefan H Heinemann
Apr 2, 2009·Circulation Journal : Official Journal of the Japanese Circulation Society·Naomasa Makita
Mar 6, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Lisa M SharkeyMiriam H Meisler
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