title: Electrophysiological characteristics of a SCN5A voltage sensors mutation R1629Q associated with Brugada syndrome.
abstract: Brugada syndrome (BrS) is an inherited arrhythmogenic syndrome leading to sudden cardiac death, partially associated with autosomal dominant mutations in SCN5A, which encodes the cardiac sodium channel alpha-subunit (Nav1.5). To date some SCN5A mutations related with BrS have been identified in voltage sensor of Nav1.5. Here, we describe a dominant missense mutation (R1629Q) localized in the fourth segment of domain IV region (DIV-S4) in a Chinese Han family. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Co-expression of Wild-type (WT) or R1629Q Nav1.5 channel and hβ1 subunit were achieved in human embryonic kidney cells by transient transfection. Sodium currents were recorded using whole cell patch-clamp protocols. No significant changes between WT and R1629Q currents were observed in current density or steady-state activation. However, hyperpolarized shift of steady-state inactivation curve was identified in cells expressing R1629Q channel (WT: V1/2 = -81.1 ± 1.3 mV, n = 13; R1629Q: V1/2 = -101.7 ± 1.2 mV, n = 18). Moreover, R1629Q channel showed enhanced intermediate inactivation and prolonged recovery time from inactivation. In summary, this study reveals that R1629Q mutation causes a distinct loss-of-function of the channel due to alter its electrophysiological characteristics, and facilitates our understanding of biophysical mechanisms of BrS.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zeng
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Zhou
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Hou
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liang
authors.forename: Ziguan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xuejing
authors.initials: X
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xie
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human