scholarly journals The Pathophysiology of Cardiac Abnormalities in Cantu Syndrome: Perspective on “The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome”

Function ◽  
2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Qadeer Aziz ◽  
Andrew Tinker
Keyword(s):  
Cardiac Hypertrophy ◽  
Potassium Channel ◽  
Channel Gain ◽  
Gain Of Function ◽  
Cardiac Abnormalities ◽  
High Output

scholarly journals The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome

Function ◽  
2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Conor McClenaghan ◽  
Yan Huang ◽  
Scot J Matkovich ◽  
Attila Kovacs ◽  
Carla J Weinheimer ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Potassium Channel ◽  
Cardiac Remodeling ◽  
Expression Patterns ◽  
Katp Channels ◽  
Gain Of Function ◽  
High Output Heart Failure ◽  
Altered Gene ◽  
Cardiac Enlargement ◽  
High Output

Abstract Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin–angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and are accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.

scholarly journals Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

2018 ◽  
Vol 24 (4) ◽  
pp. 368-380 ◽  
Author(s):  
Zachary Niday ◽  
Anastasios V. Tzingounis
Keyword(s):  
Potassium Channel ◽  
Epileptic Encephalopathy ◽  
Channel Gain ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
Gain Of Function ◽  
New Genes ◽  
Current State ◽  
Migrating Partial Seizures ◽  
Surprising Finding

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

scholarly journals Comparative gain-of-function effects of the KCNMA1-N999S mutation on human BK channel properties

2020 ◽  
Vol 123 (2) ◽  
pp. 560-570 ◽  
Author(s):  
Hans J. Moldenhauer ◽  
Katia K. Matychak ◽  
Andrea L. Meredith
Keyword(s):  
Action Potential ◽  
Potassium Channel ◽  
Antiepileptic Drug ◽  
Bk Channel ◽  
Gain Of Function ◽  
Double Mutation ◽  
Brain Physiology ◽  
Number Of Patients ◽  
Calcium Activated Potassium Channel ◽  
Channel Properties

KCNMA1, encoding the voltage- and calcium-activated potassium channel, has a pivotal role in brain physiology. Mutations in KCNMA1 are associated with epilepsy and/or dyskinesia (PNKD3). Two KCNMA1 mutations correlated with these phenotypes, D434G and N999S, were previously identified as producing gain-of-function (GOF) effects on BK channel activity. Three new patients have been reported harboring N999S, one carrying a second mutation, R1128W, but the effects of these mutations have not yet been reported under physiological K+ conditions or compared to D434G. In this study, we characterize N999S, the novel N999S/R1128W double mutation, and D434G in a brain BK channel splice variant, comparing the effects on BK current properties under a physiological K+ gradient with action potential voltage commands. N999S, N999S/R1128W, and D434G cDNAs were expressed in HEK293T cells and characterized by patch-clamp electrophysiology. N999S BK currents were shifted to negative potentials, with faster activation and slower deactivation compared with wild type (WT) and D434G. The double mutation N999S/R1128W did not show any additional changes in current properties compared with N999S alone. The antiepileptic drug acetazolamide was assessed for its ability to directly modulate WT and N999S channels. Neither the WT nor N999S channels were sensitive to the antiepileptic drug acetazolamide, but both were sensitive to the inhibitor paxilline. We conclude that N999S is a strong GOF mutation that surpasses the D434G phenotype, without mitigation by R1128W. Acetazolamide has no direct modulatory action on either WT or N999S channels, indicating that its use may not be contraindicated in patients harboring GOF KCNMA1 mutations. NEW & NOTEWORTHY KCNMA1-linked channelopathy is a new neurological disorder characterized by mutations in the BK voltage- and calcium-activated potassium channel. The epilepsy- and dyskinesia-associated gain-of-function mutations N999S and D434G comprise the largest number of patients in the cohort. This study provides the first direct comparison between D434G and N999S BK channel properties as well as a novel double mutation, N999S/R1128W, from another patient, defining the functional effects during an action potential stimulus.

scholarly journals Gain-of-function mutation in the voltage-gated potassium channel gene KCNQ1 and glucose-stimulated hypoinsulinemia - case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jinyi Zhang ◽  
Christian R. Juhl ◽  
Louise Hylten-Cavallius ◽  
Morten Salling-Olsen ◽  
Allan Linneberg ◽  
...  
Keyword(s):  
Case Report ◽  
Potassium Channel ◽  
Gain Of Function ◽  
Voltage Gated ◽  
Channel Gene ◽  
Potassium Channel Gene

scholarly journals Increased tolerance to stress in cardiac expressed gain-of-function of adenosine triphosphate–sensitive potassium channel subunit Kir6.1

2016 ◽  
Vol 206 (2) ◽  
pp. 460-465 ◽  
Author(s):  
Matthew C. Henn ◽  
M. Burhan Janjua ◽  
Haixia Zhang ◽  
Evelyn M. Kanter ◽  
Carol M. Makepeace ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Adenosine Triphosphate ◽  
Gain Of Function

Myocytes with Gain-of-Function of Adenosine Triphosphate-Sensitive Potassium Channel Subunit Kir6.1 Have Altered Response to Stress of Hyperkalemic Cardioplegia

2015 ◽  
Vol 221 (4) ◽  
pp. S25
Author(s):  
Matthew C. Henn ◽  
M. Burhan Janjua ◽  
Haixia Zhang ◽  
Evelyn M. Kanter ◽  
Carol M. Makepeace ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Adenosine Triphosphate ◽  
Gain Of Function ◽  
Response To Stress ◽  
Altered Response

scholarly journals Age Dependent Regulation of Cardiac Sodium Channel Gain of Function

2019 ◽  
Vol 116 (3) ◽  
pp. 98a
Author(s):  
Madison B. Nowak ◽  
David Ryan King ◽  
Steven Poelzing ◽  
Seth H. Weinberg
Keyword(s):  
Sodium Channel ◽  
Channel Gain ◽  
Gain Of Function ◽  
Cardiac Sodium Channel ◽  
Age Dependent

scholarly journals Early-Onset Epileptic Encephalopathy Caused by Gain-of-Function Mutations in the Voltage Sensor of Kv7.2 and Kv7.3 Potassium Channel Subunits

2015 ◽  
Vol 35 (9) ◽  
pp. 3782-3793 ◽  
Author(s):  
F. Miceli ◽  
M. V. Soldovieri ◽  
P. Ambrosino ◽  
M. De Maria ◽  
M. Migliore ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Early Onset ◽  
Epileptic Encephalopathy ◽  
Voltage Sensor ◽  
Gain Of Function

scholarly journals Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome

Heart Rhythm ◽  
2011 ◽  
Vol 8 (7) ◽  
pp. 1024-1032 ◽  
Author(s):  
John R. Giudicessi ◽  
Dan Ye ◽  
David J. Tester ◽  
Lia Crotti ◽  
Alessandra Mugione ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Brugada Syndrome ◽  
Outward Current ◽  
Transient Outward Current ◽  
Gain Of Function

scholarly journals P1590Ischemia-induced small-conductance calcium-activated potassium channel activation deteriorates ventricular arrhythmias in cardiac hypertrophy through the CaMKII-dependent pathway

EP Europace ◽  
2017 ◽  
Vol 19 (suppl_3) ◽  
pp. iii338-iii339
Author(s):  
T. Tenma ◽  
H. Mitsuyama ◽  
M. Watanabe ◽  
K. Mizukami ◽  
R. Kamada ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Potassium Channel ◽  
Ventricular Arrhythmias ◽  
Channel Activation ◽  
Calcium Activated Potassium Channel ◽  
Dependent Pathway ◽  
Small Conductance
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