Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2

Korkosh, Vyacheslav S.; Kiselev, Artem; Mikhaylov, Evgeny N.; Kostareva, Anna; Zhorov, Boris S.

doi:10.3389/fphys.2019.00335

Cited by 14 publications

(6 citation statements)

References 69 publications

(109 reference statements)

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“…Following voltage-dependent channel activation, the cytoplasmic face of DIIS0 would perturb and shift DIIS0-bound AID toward the pore axis. The AID-linked DIS6 would bend at the flexible G402 and G406, facilitating the activation-gate closure and thus the VDI [ 36 ]. The R511 position in DIIS0 may form a salt bridge with acidic residues in positions immediately C-terminal to the AID.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the R511Q mutation would destroy the salt bridges and weaken the DIIS0-AID contact, retarding the AID displacement thus delaying the VDI. Regarding the interaction of AID and β-subunit, four basic residues (R514, R515, R518 and K522) in DIIS0 are thought to provide large contributions to the interaction energy between AID and β-subunit, while R511 is not [ 36 ]. Further studies are required to reveal whether or not R511Q affects the DIIS0-AID-β-subunit interaction.…”

Section: Discussionmentioning

confidence: 99%

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Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

Nakajima

Kawabata‐Iwakawa²,

Tamura³

et al. 2022

PLoS ONE

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Background Gain-of-function mutations in CACNA1C encoding Cav1.2 cause syndromic or non-syndromic type-8 long QT syndrome (LQTS) (sLQT8 or nsLQT8). The cytoplasmic domain (D)Ⅰ-Ⅱ linker in Cav1.2 plays a pivotal role in calcium channel inactivation, and mutations in this site have been associated with sLQT8 (such as Timothy syndrome) but not nsLQT8. Objective Since we identified a novel CACNA1C mutation, located in the DⅠ-Ⅱ linker, associated with nsLQTS, we sought to reveal its biophysical defects. Methods Target panel sequencing was employed in 24 genotype-negative nsLQTS probands (after Sanger sequencing) and three family members. Wild-type (WT) or R511Q Cav1.2 was transiently expressed in tsA201 cells, then whole-cell Ca2+ or Ba2+ currents (ICa or IBa) were recorded using whole-cell patch-clamp techniques. Results We identified two CACNA1C mutations, a previously reported R858H mutation and a novel R511Q mutation located in the DⅠ-Ⅱ linker. Four members of one nsLQTS family harbored the CACNA1C R511Q mutation. The current density and steady-state activation were comparable to those of WT-ICa. However, persistent currents in R511Q-ICa were significantly larger than those of WT-ICa (WT at +20 mV: 3.3±0.3%, R511Q: 10.8±0.8%, P<0.01). The steady-state inactivation of R511Q-ICa was weak in comparison to that of WT-ICa at higher prepulse potentials, resulting in increased window currents in R511Q-ICa. Slow component of inactivation of R511Q-ICa was significantly delayed compared to that of WT-ICa (WT-tau at +20 mV: 81.3±3.3 ms, R511Q-tau: 125.1±5.0 ms, P<0.01). Inactivation of R511Q-IBa was still slower than that of WT-IBa, indicating that voltage-dependent inactivation (VDI) of R511Q-ICa was predominantly delayed. Conclusions Delayed VDI, increased persistent currents, and increased window currents of R511Q-ICa cause nsLQT8. Our data provide novel insights into the structure-function relationships of Cav1.2 and the pathophysiological roles of the DⅠ-Ⅱ linker in phenotypic manifestations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

Nakajima

Kawabata‐Iwakawa²,

Tamura³

et al. 2022

PLoS ONE

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“…We used the cryo-EM structure of rat Nav1.5 channel in the open state [ 18 ] to transform the PM of the insect channels in the open state using the methodology of large-scale in silico transformations of PM in full-fledged channel models, as described by the authors of [ 21 ]. Voltage-sensing domains were transformed from the activated to resting states, as described in the study in [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel

Zhorov

Dong

2022

Insects

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Pyrethroid insecticides stabilize the open state of insect sodium channels. Previous mutational, electrophysiological, and computational analyses led to the development of homology models predicting two pyrethroid receptor sites, PyR1 and PyR2. Many of the naturally occurring sodium channel mutations, which confer knockdown resistance (kdr) to pyrethroids, are located within or close to these receptor sites, indicating that these mutations impair pyrethroid binding. However, the mechanism of the state-dependent action of pyrethroids and the mechanisms by which kdr mutations beyond the receptor sites confer resistance remain unclear. Recent advances in protein structure prediction using the AlphaFold2 (AF2) neural network allowed us to generate a new model of the mosquito sodium channel AaNav1-1, with the activated voltage-sensing domains (VSMs) and the presumably inactivated pore domain (PM). We further employed Monte Carlo energy minimizations to open PM and deactivate VSM-I and VSM-II to generate additional models. The docking of a Type II pyrethroid deltamethrin in the models predicted its interactions with many known pyrethroid-sensing residues in the PyR1 and PyR2 sites and revealed ligand-channel interactions that stabilized the open PM and activated VSMs. Our study confirms the predicted two pyrethroid receptor sites, explains the state-dependent action of pyrethroids, and proposes the mechanisms of the allosteric effects of various kdr mutations on pyrethroid action. The AF2-based models may assist in the structure-based design of new insecticides.

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“…Some of them are associated with phenotypic syndromes and specific ECG features ( Table 1 ). These include Andersen–Tawil syndrome (LQT7, KCNJ2 ) in which skeletal developmental abnormalities are observed [ 54 ]; Timothy syndrome (LQT8, CACNA1C ) with characteristic neurological, facial and limb features [ 106 ] and JLNS syndrome, associated with sensorineural deafness ( KCNQ1-KCNE1 genes) [ 107 ]. Although the association of pathogenic variants in these genes with multiorganic syndromes is clear, the level of evidence for the specific cardiac phenotype is not so clear, and further studies are needed [ 10 ].…”

Section: Long Qt Syndromementioning

confidence: 99%

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

et al. 2022

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Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2

Cited by 14 publications

References 69 publications

Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

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