A5057770335- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Congenital heart defects research
- Congenital Heart Disease Studies
- Receptor Mechanisms and Signaling
- Genomics and Rare Diseases
- Neuroscience and Neuropharmacology Research
- Cardiomyopathy and Myosin Studies
- Ion Transport and Channel Regulation
- Cardiovascular Function and Risk Factors
- Cardiac Arrhythmias and Treatments
- Neuroscience and Neural Engineering
- Pulmonary Hypertension Research and Treatments
- Cardiac pacing and defibrillation studies
- Cardiovascular Effects of Exercise
- Genomic variations and chromosomal abnormalities
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Neuroscience of respiration and sleep
- Machine Learning in Healthcare
- Cardiovascular Conditions and Treatments
- Cardiac Valve Diseases and Treatments
- Heart Failure Treatment and Management
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
University of Utah
2016-2025
University of Utah Health Care
2024
Harrison Medical Center
2007-2024
Vanderbilt University Medical Center
2024
Primary Children's Hospital
1998-2023
Tristan Technologies (United States)
2019-2021
Yale University
2020
Washington Center
2018
University of Washington
2018
Universidad de Colima
2016
Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS caused mutations in KCNJ2, which encodes the inward rectifier K+ channel Kir2.1. In this report, we functional consequences of three novel seven previously described KCNJ2 using two-microelectrode voltage-clamp technique correlated findings clinical phenotype. All resulted loss function...
Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array birth defects. Although 90% affected individuals share same three megabase deletion, their phenotype highly variable and includes craniofacial cardiovascular anomalies, hypoplasia or aplasia thymus deficiency T cells, hypocalcemia parathyroids, variety central nervous system abnormalities. Because ablation neural crest chicks produces many features deletion 22q11...
Background— The ECG features of Andersen-Tawil syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define mutation carriers, determine whether characteristic T-U–wave patterns exist, and establish T-U predict the ATS1 genotype. Methods Results— In phase I, evaluation morphology in ECGs 39 carriers identified patterns: prolonged terminal T downslope, wide junction, biphasic enlarged U waves. II, genotype prediction by pattern was...
Vertebrate hearts depend on highly specialized cardiomyocytes that form the cardiac conduction system (CCS) to coordinate chamber contraction and drive blood efficiently unidirectionally throughout organism. Defects in this wiring can lead syncope sudden death. Thus, a greater understanding of development may help prevent these devastating clinical outcomes. Utilizing cardiac-specific fluorescent calcium indicator zebrafish transgenic line, Tg(cmlc2:gCaMP)s878, allows for vivo optical...
Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model inherited LQTS does not exist. The zebrafish powerful vertebrate used dissect molecular pathways cardiovascular development and disease. Because fundamental electrical properties the heart are remarkably similar those human heart, may be for studying Here we describe molecular, cellular, electrophysiological basis mutant...
Mutations in KCNJ2, the gene encoding inward-rectifying K+ channel Kir2.1, cause cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not identified.Seventeen probands presenting with symptoms characteristic ATS were evaluated clinically screened mutations KCNJ2. The results mutation analysis combined those from previously studied...
TBX3 is critical for human development: mutations in cause congenital anomalies patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles Tbx3 development function of the cardiac conduction system. The mechanisms underlying functional development, maturation, maintenance system are not well understood. We tested requirements these processes. generated a unique series hypomorphic conditional mouse mutants varying levels locations activity within heart, developed...
Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well recessive or dominant variants that explain the phenotype. However, filtering strategies and software used prioritize high-confidence vary from study study. an effort establish recommendations disease research, we explore effective guidelines variant (SNP INDEL) report expected number candidates dominant, recessive, autosomal modes inheritance. We derived these using two large...
Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, structural of heart great vessels. The rapidly expanding availability clinical genetic testing leverages decades research into origins these diseases, helping inform diagnosis, management, prognosis. Although a number guidelines statements detail best practices for testing, there is paucity pediatric-focused addressing unique...
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the contribution broad range CHD phenotypes has limited. We analyzed whole exome sequences 5,424 probands. Rare damaging RGs were estimated at least 2.2% CHD, greater enrichment among laterality (5.4%) versus other subsets (1.4%). Among 108 curated human genes,...
Andersen-Tawil syndrome is a skeletal and cardiac muscle disease with developmental features caused by mutations in the inward rectifier K+ channel gene KCNJ2. Patients harboring these exhibit extremely variable expressivities. To explore whether can be correlated specific patient phenotype, we expressed both wild-type (WT) mutant genes cloned into bi-cistronic vector. Functional expression human embryonic kidney 293 cells showed that none of channels express current when present alone. When...
Outward movement of the voltage sensor is coupled to activation in voltage-gated ion channels; however, precise mechanism and structural basis this gating event are poorly understood. Potential insight into coupling was provided by our previous finding that mutation Lys a single residue (Asp540) located S4-S5 linker endowed HERG (human ether-a-go-go-related gene) K+ channels with unusual ability open response membrane depolarization hyperpolarization voltage-dependent manner. We hypothesized...
The time course and voltage dependence of inactivation KvLQT1 channels expressed in Xenopus oocytes were studied using two‐microelectrode voltage‐clamp techniques. Tail current analysis was used to characterize the kinetics channel deactivation. constant for recovery from dependent varied 30 ± 2 ms at −90 mV 36 1 −30 mV. deactivation 186 21 986 43 over same range. Inactivation incomplete, reducing fully activated by 35 % +40 half‐maximal −18 onset during a single depolarization +20...
Block of human ether-a-go-go related gene (HERG) K<sup>+</sup> channels by a variety medications has been linked to acquired long QT syndrome, disorder cardiac repolarization that predisposes lethal arrhythmias. The drug-binding site is composed residues face into the central cavity channel. Two aromatic located on S6 domain (Tyr652 and Phe656) are particularly important structural determinants drug block. role pore helix (Thr623, Ser624, Val625) less clear. In this study, we compared...
Voltage-gated channels are normally opened by depolarization and closed repolarization of the membrane. Despite sharing significant sequence homology with voltage-gated K + channels, gating hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker has opposite dependence on membrane potential: hyperpolarization opens, whereas closes, these channels. The mechanism structural basis process that couples voltage sensor movement to HCN channel opening closing is not understood. On our...
The ductus arteriosus is a vital fetal structure allowing blood ejected from the right ventricle to bypass pulmonary circulation in utero. Closure of at birth, essential for postnatal adaptation, initiated by an increase oxygen (O2) tension. We recently demonstrated presence O2-sensitive potassium channels and adult which regulate vascular tone response changes O2 In this study, we assessed cellular mechanisms underlying O2-induced constriction late-gestation rabbits. report that reversibly...
Although chloroquine remains an important therapeutic agent for treatment of malaria in many parts the world, its safety margin is very narrow. Chloroquine inhibits cardiac inward rectifier K + current I K1 and can induce lethal ventricular arrhythmias. In this study, we characterized biophysical molecular basis block Kir2.1 channels that underlie . The voltage- -dependence implied binding site was located within ion-conduction pathway. Site-directed mutagenesis revealed location...