Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

Abstract

Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K+ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-à-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations.

Dysregulation of N-terminal acetylation causes cardiac arrhythmia and cardiomyopathy

“…We systemically examined each major ionic current underlying the cardiac action potential to identify dysregulation of both INa and IKs in mutant NAA10 iPSC-CMs. This unique combination induces significant repolarization abnormalities consistent with a high-risk clinical phenotype (QT > 500msec, recurrent TdP) and similar to patients with complex heterozygosity and missense mutations in both KCNQ1 and SCN5A 41 . In addition to decreased IKs, INaL was increased as a major mechanism for NAA10-mediated dysregulation of the sodium channel complex.…”

Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes

“…Molecular simulations are widely used for predicting protein function by animating proteins based on their three-dimensional structure and molecular interactions. Recent molecular dynamic simulations of Kv7.1 and Kv11.1 channel protein structures have provided insights into how individual missense mutations perturb the channel structure in Kv7.1 and Kv11.1 [134,135,[138][139][140]. As such, computational tools are beginning to serve as useful tools for mapping how mutations in Kv7.1 and Kv11.1 channel proteins may impact channel structure to cause dysfunction.…”

“…Molecular dynamics can specifically predict how proteins dynamically ebb and flow in response to long-and short-range physical interactions by solving equations of motion. Structural simulations of LQT1-and LQT2linked mutations are expected to identify the dynamic conformations in the Kv7.1 and Kv11.1 protein structures that associate with mutation-specific mechanisms for channel dysfunction [71,134,135,140,[142][143][144].…”