A Novel SCN5A Variant Associated with Abnormal Repolarization, Atrial Fibrillation, and Reversible Cardiomyopathy

Cardiology ◽  
2018 ◽  
Vol 140 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Kim Boddum ◽  
Arnela Saljic ◽  
Thomas Jespersen ◽  
Alex Hørby Christensen
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Manifestations ◽  
Persistent Atrial Fibrillation ◽  
Inactivation Kinetics ◽  
Loss Of Function ◽  
Na Current ◽  
Structural Abnormalities ◽  
Kinetics Of

A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodium channel encoded by the SCN5A gene. In this study, we report a novel loss-of-function SCN5A variant, p.Ile1343Val (c.4027A>G), identified in a 42-year-old proband who presented with an unusual ECG with abnormal repolarization with biphasic T-waves in anteroseptal leads, persistent atrial fibrillation (AF), intermittent left bundle branch block (LBBB), and reversible cardiomyopathy. The patient did not meet the diagnostic criteria for Brugada syndrome, long QT syndrome, or any other known SCN5A-associated phenotype. Characterization of the biophysical properties of the variant by in vitro patch clamp experiments revealed a reduced Na+ current with no effect on the inactivation kinetics of the channel. This loss-of-function of Na+ current could explain the intermittent LBBB as well as the AF. In conclusion, we describe a unique combination of electrical and structural abnormalities associated with a novel SCN5A variant. Our findings broaden the spectrum of cardiac phenotypes associated with SCN5A channelopathy, underlining the complex clinical manifestations of genetic variations within this gene.

scholarly journals Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2390
Author(s):  
Ankush Borlepawar ◽  
Nesrin Schmiedel ◽  
Matthias Eden ◽  
Lynn Christen ◽  
Alexandra Rosskopf ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Loss Of Function ◽  
Interaction Partners ◽  
Lysosome Related Organelles ◽  
The Stability ◽  
Schizophrenia Susceptibility

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

scholarly journals Identification and Characterization of Sites Where Persistent Atrial Fibrillation Is Terminated by Localized Ablation

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Junaid A.B. Zaman ◽  
William H. Sauer ◽  
Mahmood I. Alhusseini ◽  
Tina Baykaner ◽  
Ryan T. Borne ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Persistent Atrial Fibrillation ◽  
Identification And Characterization

scholarly journals Characterization of a Spontaneous 9.5-Kilobase-Deletion Mutant of Murine Gammaherpesvirus 68 Reveals Tissue-Specific Genetic Requirements for Latency

2002 ◽  
Vol 76 (13) ◽  
pp. 6532-6544 ◽  
Author(s):  
Eric T. Clambey ◽  
Herbert W. Virgin ◽  
Samuel H. Speck
Keyword(s):  
Deletion Mutant ◽  
Latent Infection ◽  
Loss Of Function ◽  
Murine Gammaherpesvirus ◽  
Peritoneal Cells ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Murine gammaherpesvirus 68 (γHV68 [also known as MHV-68]) establishes a latent infection in mice, providing a small-animal model with which to identify host and viral factors that regulate gammaherpesvirus latency. While γHV68 establishes a latent infection in multiple tissues, including splenocytes and peritoneal cells, the requirements for latent infection within these tissues are poorly defined. Here we report the characterization of a spontaneous 9.5-kb-deletion mutant of γHV68 that lacks the M1, M2, M3, and M4 genes and eight viral tRNA-like genes. Previously, this locus has been shown to contain the latency-associated M2, M3, and viral tRNA-like genes. Through characterization of this mutant, we found that the M1, M2, M3, M4 genes and the viral tRNA-like genes are dispensable for (i) in vitro replication and (ii) the establishment and maintenance of latency in vivo and reactivation from latency following intraperitoneal infection. In contrast, following intranasal infection with this mutant, there was a defect in splenic latency at both early and late times, a phenotype not observed in peritoneal cells. These results indicate (i) that there are different genetic requirements for the establishment of latency in different latent reservoirs and (ii) that the genetic requirements for latency depend on the route of infection. While some of these phenotypes have been observed with specific mutations in the M1 and M2 genes, other phenotypes have never been observed with the available γHV68 mutants. These studies highlight the importance of loss-of-function mutations in defining the genetic requirements for the establishment and maintenance of herpesvirus latency.

scholarly journals Inactivation kinetics of macroscopic Na+ current in voltage-clamped embryonic chick heart cell.

1993 ◽  
Vol 61 ◽  
pp. 100
Author(s):  
Hideajo Sada ◽  
Kotaro Tanaka ◽  
Hisamitsu Ujihara ◽  
Yasue Yamada ◽  
Takashi Ban
Keyword(s):  
Inactivation Kinetics ◽  
Heart Cell ◽  
Embryonic Chick ◽  
Na Current ◽  
Chick Heart ◽  
Embryonic Chick Heart ◽  
Kinetics Of

scholarly journals Characterization of the Global Stabilizing Substitution A77V and Its Role in the Evolution of CTX-M β-Lactamases

2015 ◽  
Vol 59 (11) ◽  
pp. 6741-6748 ◽  
Author(s):  
Meha P. Patel ◽  
Bartlomiej G. Fryszczyn ◽  
Timothy Palzkill
Keyword(s):  
Antibiotic Resistance ◽  
Adaptive Mutation ◽  
Common Mechanism ◽  
Antibiotic Hydrolysis ◽  
The Stability ◽  
Kinetics Of ◽  
M 14

ABSTRACTThe widespread use of oxyimino-cephalosporin antibiotics drives the evolution of the CTX-M family of β-lactamases that hydrolyze these drugs and confer antibiotic resistance. Clinically isolated CTX-M enzymes carrying the P167S or D240G active site-associated adaptive mutation have a broadened substrate profile that includes the oxyimino-cephalosporin antibiotic ceftazidime. The D240G substitution is known to reduce the stability of CTX-M-14 β-lactamase, and the P167S substitution is shown here to also destabilize the enzyme. Proteins are marginally stable entities, and second-site mutations that stabilize the enzyme can offset a loss in stability caused by mutations that enhance enzyme activity. Therefore, the evolution of antibiotic resistance enzymes can be dependent on the acquisition of stabilizing mutations. The A77V substitution is present in CTX-M extended-spectrum β-lactamases (ESBLs) from a number of clinical isolates, suggesting that it may be important in the evolution of antibiotic resistance in this family of β-lactamases. In this study, the effects of the A77V substitution in the CTX-M-14 model enzyme were characterized with regard to the kinetic parameters for antibiotic hydrolysis as well as enzyme expression levelsin vivoand protein stabilityin vitro. The A77V substitution has little effect on the kinetics of oxyimino-cephalosporin hydrolysis, but it stabilizes the CTX-M enzyme and compensates for the loss of stability resulting from the P167S and D240G mutations. The acquisition of global stabilizing mutations, such as A77V, is an important feature in β-lactamase evolution and a common mechanism in protein evolution.

scholarly journals A role for Rab5 in structuring the endoplasmic reticulum

2007 ◽  
Vol 178 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Anjon Audhya ◽  
Arshad Desai ◽  
Karen Oegema
Keyword(s):  
Endoplasmic Reticulum ◽  
Caenorhabditis Elegans ◽  
Nuclear Envelope ◽  
Rab Gtpases ◽  
C Elegans ◽  
Rab Family ◽  
Kinetics Of

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.

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