Journal article
Transfer RNA mediated restoration of potassium conductance and electrical correction in premature termination Long-QT Syndrome hERG mutants
Molecular therapy. Nucleic acids, Vol.34, 102032
12/12/2023
DOI: 10.1016/j.omtn.2023.102032
PMCID: PMC10568093
PMID: 37842167
Abstract
Disease-causing Premature Termination Codons (PTCs) individually disrupt the functional expression of hundreds of genes and represent a pernicious clinical challenge. In the heart, loss of function mutations in the hERG potassium channel account for approximately 30% of Long-QT Syndrome arrhythmia, a lethal cardiac disorder with limited treatment options. Premature termination of ribosomal translation produces a truncated and, for potassium channels, a potentially dominant negative protein which impairs the functional assembly of the wild-type homotetrameric hERG channel complex. We used high-throughput flow cytometry and patch-clamp electrophysiology to assess the trafficking and voltage-dependent activity of hERG channels carrying patient PTC variants that have been corrected by anticodon engineered tRNA. Adenoviral-mediated expression of mutant hERG channels in cultured adult guinea pig cardiomyocytes prolonged action potential durations and this deleterious effect was corrected upon adenoviral delivery of a human ArgUGA tRNA to restore full-length hERG protein. The results demonstrate mutation specific, context agnostic PTC correction and elevate the therapeutic potential of this approach for rare genetic diseases caused by stop codons.
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Loss of function mutations in the hERG potassium channel account for approximately 30% of Long-QT Syndrome arrhythmia, a lethal cardiac disorder with limited treatment options. Blomquist, Niu and colleagues used anticodon engineered tRNA to correct patient nonsense mutations in hERG channels, elevating this therapeutic strategy for other rare genetic diseases.
Details
- Title: Subtitle
- Transfer RNA mediated restoration of potassium conductance and electrical correction in premature termination Long-QT Syndrome hERG mutants
- Creators
- Viggo G. Blomquist - Columbia University Irving Medical CenterJacqueline Niu - Columbia University Irving Medical CenterPapiya Choudhury - Columbia University Irving Medical CenterAhmad Al Saneh - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, IowaHenry M. Colecraft - Columbia University Irving Medical CenterChristopher A. Ahern - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Nucleic acids, Vol.34, 102032
- DOI
- 10.1016/j.omtn.2023.102032
- PMID
- 37842167
- PMCID
- PMC10568093
- NLM abbreviation
- Mol Ther Nucleic Acids
- ISSN
- 2162-2531
- eISSN
- 2162-2531
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust; DOI: 10.13039/100006474, name: Columbia University; DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1 HL142111; DOI: 10.13039/100000054, name: National Cancer Institute, award: P30CA013696
- Language
- English
- Electronic publication date
- 09/2023
- Date published
- 12/12/2023
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984466747302771
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