Characterization of the novel heterozygous SCN5A genetic variant Y739D associated with Brugada syndrome.

Autor: Zaytseva AK; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia.; Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia., Kiselev AM; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia.; Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia., Boitsov AS; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia., Fomicheva YV; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia., Pavlov GS; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia., Zhorov BS; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia.; Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, L8S 4K1, Canada., Kostareva AA; Almazov National Medical Research Centre, St. Petersburg, 197341, Russia.; Department of Woman and Child Health, Karolinska Institute, Stockholm, 17176, Sweden.
Jazyk: angličtina
Zdroj: Biochemistry and biophysics reports [Biochem Biophys Rep] 2022 Mar 11; Vol. 30, pp. 101249. Date of Electronic Publication: 2022 Mar 11 (Print Publication: 2022).
DOI: 10.1016/j.bbrep.2022.101249
Abstrakt: Genetic variants in SCN5A gene were identified in patients with various arrhythmogenic conditions including Brugada syndrome. Despite significant progress of last decades in studying the molecular mechanism of arrhythmia-associated SCN5A mutations, the understanding of relationship between genetics, electrophysiological consequences and clinical phenotype is lacking. We have found a novel genetic variant Y739D in the SCN5A- encoded sodium channel Na v 1.5 of a male patient with Brugada syndrome (BrS). The objective of the study was to characterize the biophysical properties of Na v 1.5-Y739D and provide possible explanation of the phenotype observed in the patient. The WT and Y739D channels were heterologously expressed in the HEK-293T cells and the whole-cell sodium currents were recorded. Substitution Y739D reduced the sodium current density by 47 ± 2% at -20 mV, positively shifted voltage-dependent activation, accelerated both fast and slow inactivation, and decelerated recovery from the slow inactivation. The Y739D loss-of-function phenotype likely causes the BrS manifestation. In the hNa v 1.5 homology models, which are based on the cryo-EM structure of rat Na v 1.5 channel, Y739 in the extracellular loop IIS1-S2 forms H-bonds with K1381 and E1435 and pi-cation contacts with K1397 (all in loop IIIS5-P1). In contrast, Y739D accepts H-bonds from K1397 and Y1434. Substantially different contacts of Y739 and Y739D with loop IIIS5-P1 would differently transmit allosteric signals from VSD-II to the fast-inactivation gate at the N-end of helix IIIS5 and slow-inactivation gate at the C-end of helix IIIP1. This may underlie the atomic mechanism of the Y739D channel dysfunction.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2022 Published by Elsevier B.V.)
Databáze: MEDLINE
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