A5076053080- Cardiomyopathy and Myosin Studies
- Cardiac electrophysiology and arrhythmias
- Cardiovascular Effects of Exercise
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- Genomics and Rare Diseases
- ATP Synthase and ATPases Research
- Blood Coagulation and Thrombosis Mechanisms
- Congenital heart defects research
- Metabolism and Genetic Disorders
- Ion channel regulation and function
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Advanced biosensing and bioanalysis techniques
- Genetic Associations and Epidemiology
- Protease and Inhibitor Mechanisms
- Cardiovascular Function and Risk Factors
- Genomics and Phylogenetic Studies
- Monoclonal and Polyclonal Antibodies Research
- Sleep and Wakefulness Research
- Cardiac Structural Anomalies and Repair
- Endoplasmic Reticulum Stress and Disease
- Biochemical and Structural Characterization
- Cardiac Fibrosis and Remodeling
- BRCA gene mutations in cancer
Stanford University
2013-2025
Stanford Medicine
2024
Johns Hopkins Medicine
2023
Johns Hopkins University
2023
Stanford Health Care
2012-2018
Center for Inherited Blood Disorders
2018
Indiana University – Purdue University Indianapolis
2017
University of Pennsylvania
2017
Icahn School of Medicine at Mount Sinai
2017
Madras Medical Mission
2017
Utilizing site-directed mutagenesis, 77 charged and polar residues that are highly exposed on the surface of human thrombin were systematically substituted with alanine. Functional assays using mutants identified required for recognition cleavage procoagulant substrate fibrinogen (Lys21, Trp50, Lys52, Asn53+Thr55, Lys65, His66, Arg68, Tyr71, Arg73, Lys77, Lys106+Lys107, Asp193+Lys196, Glu202, Glu229, Arg233, Asp234) anticoagulant protein C Arg233), interactions cofactor thrombomodulin...
The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because uncertainty regarding population genetic variation and a surprising amount tolerance the genome even loss-of-function variants. We hypothesized that cardiomyopathy might particularly resistant accumulation variation.We analyzed rates single nucleotide all known from exomes >5000 individuals National Heart, Lung, Blood Institute's Exome Sequencing Project, as well...
Significance Most genetic studies and clinical testing do not look for the possibility of mosaic variation. The form long-QT syndrome (LQTS) can result in life-threatening arrhythmias, but 30% patients have a diagnosis. We performed deep characterization variant an infant with perinatal LQTS developed computational model showing how abnormal cellular repolarization only 8% heart cells may cause arrhythmia. Finally we looked at prevalence mosaicism among LQTS; population 7,500 individuals...
Previous alanine scanning mutagenesis of thrombin revealed that substitution residues W50, K52, E229, and R233 (W60d, K60f, E217, R221 in chymotrypsinogen numbering) with altered the substrate specificity to favor anticoagulant protein C. Saturation mutagenesis, which were each substituted all 19 naturally occurring amino acids, resulted identification a single mutation, E229K, shifted by 130-fold activation C over procoagulant fibrinogen. E229K was also less effective activating platelets...
ABSTRACT The underrepresentation of different ancestry groups in large genomic datasets creates difficulties interpreting the pathogenicity monogenic variants. Genetic testing for individuals with non-European results higher rates uncertain variants and a greater risk misclassification. We report rare variant cardiac troponin T gene, TNNT2 ; NM_001001430.3: c.571-1G>A (rs483352835) identified via research-based whole exome sequencing two unrelated probands Oceanian phenotypes. disrupts...
The thrombin aptamer is a single-stranded DNA of 15 nucleotides that was identified by the selection thrombin-binding molecules from large combinatorial library oligonucleotides. This prototype has unique double G-tetrad structure capable inhibiting at nanomolar concentrations through binding to specific region within exosite I. Substitution arginine 70 in I with glutamic acid effectively eliminated aptamer. In contrast, aptamers selected against R70E were able bind and inhibit both...
PurposeBiallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.MethodsSynthesis of clinical and molecular data concerning 34 five previously reported 12 novel variants, 11 which were functionally characterized.ResultsAmong individuals, only 6 remain...
ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking
BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that associated with rare, loss-of-function variants in SCN5A . Interpreting the pathogenicity of missense challenging, and ≈79% ClinVar are currently classified as uncertain significance. Automated patch clamp technology enables high-throughput functional studies ion channel can provide evidence for variant reclassification. METHODS: An vitro –Brugada automated assay was independently performed at Vanderbilt University...
Abstract Alpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca 2+ -signaling. In heterozygous indel cells, truncated protein...