Mechanistic insights into the interaction of cardiac sodium channel Nav1.5 with MOG1 and a new molecular mechanism for Brugada syndrome.

Heart rhythm 2022 Mar

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Mutations in cardiac sodium channel Nav1.5 cause Brugada syndrome (BrS). MOG1 is a chaperone that binds to Nav1.5, facilitates Nav1.5 trafficking to the cell surface, and enhances the amplitude of sodium current INa. The purpose of this study was to identify structural elements involved in MOG1-Nav1.5 interaction and their relevance to the pathogenesis of BrS. Systematic analyses of large deletions, microdeletions, and point mutations, and glutathione S-transferases pull-down, co-immunoprecipitation, cell surface protein quantification, and patch-clamping of INa were performed. Large deletion analysis defined the MOG1-Nav1.5 interaction domain to amino acids S476-H585 of Nav1.5 Loop I connecting transmembrane domains I and II. Microdeletion and point mutation analyses further defined the domain to F530T531F532R533R534R535. Mutations F530A, F532A, R533A, and R534A, but not T531A and R535A, significantly reduced MOG1-Nav1.5 interaction and eliminated MOG1-enhanced INa. Mutagenesis analysis identified D24, E36, D44, E53, and E101A of MOG1 as critical residues for interaction with Nav1.5 Loop I. We then characterized 3 mutations at the MOG1-Nav1.5 interaction domain: p.F530V, p.F532C, and p.R535Q reported from patients with long QT syndrome and BrS. We found that p.F532C reduced MOG1-Nav1.5 interaction and eliminated MOG1 function on INa; p.R535Q is also a loss-of-function mutation that reduces INa amplitude in a MOG1-independent manner, whereas p.F530V is benign as it does not have an apparent effect on MOG1 and INa. Our findings define the MOG1-Nav1.5 interaction domain to a 5-amino-acid motif of F530T531F532R533R534 in Loop I. Mutation p.F532C associated with BrS abolishes Nav1.5 interaction with MOG1 and reduces MOG1-enhanced INa density, thereby uncovering a novel molecular mechanism for the pathogenesis of BrS. Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Citation

Hongbo Xiong, Xuemei Bai, Zhuang Quan, Dong Yu, Hongfu Zhang, Chi Zhang, Lina Liang, Yufeng Yao, Qin Yang, Zhijie Wang, Longfei Wang, Yuan Huang, Hui Li, Xiang Ren, Xin Tu, Tie Ke, Chengqi Xu, Qing K Wang. Mechanistic insights into the interaction of cardiac sodium channel Nav1.5 with MOG1 and a new molecular mechanism for Brugada syndrome. Heart rhythm. 2022 Mar;19(3):478-489