Back to Search
Start Over
Mechanistic insights into the interaction of cardiac sodium channel Nav1.5 with MOG1 and a new molecular mechanism for Brugada syndrome
- Source :
- Heart Rhythm. 19:478-489
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- Background Mutations in cardiac sodium channel Nav1.5 cause Brugada syndrome (BrS). MOG1 is a chaperon that binds to Nav1.5, facilitates Nav1.5 trafficking to cell surface, and enhances amplitude of sodium current INa. Objective To identify structural elements involved in MOG1-Nav1.5 interaction and their relevance to the pathogenesis of BrS. Methods Systematic analyses of large deletions, microdeletions and point mutations. Glutathione S-transferases pull-down, co-immunoprecipitation, cell surface protein quantification and patch-clamping of INa. Results 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 three mutations at the MOG1-Nav1.5 interaction domain, p.F530V, p.F532C and p.R535Q reported from patients with LQTS 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 apparent effect on MOG1 and INa. Conclusions 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.
Details
- ISSN :
- 15475271
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Heart Rhythm
- Accession number :
- edsair.doi...........52f39b916d462353b780d6144e317e01