Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death

Authors

  • John R. Giudicessi,

    1. Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    2. Division of Pediatric Cardiology, Department of Pediatrics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    3. Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    4. Mayo Medical School, Mayo Clinic, Rochester, Minnesota
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    • These authors contributed equally to the research and are joint first authors.

  • Dan Ye,

    1. Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    2. Division of Pediatric Cardiology, Department of Pediatrics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    3. Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
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    • These authors contributed equally to the research and are joint first authors.

  • Chad J. Kritzberger,

    1. Mayo Medical School, Mayo Clinic, Rochester, Minnesota
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  • Vladislav V. Nesterenko,

    1. Masonic Medical Research Laboratory, Utica, New York
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  • David J. Tester,

    1. Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    2. Division of Pediatric Cardiology, Department of Pediatrics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    3. Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
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  • Charles Antzelevitch,

    1. Masonic Medical Research Laboratory, Utica, New York
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  • Michael J. Ackerman

    Corresponding author
    1. Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    2. Division of Pediatric Cardiology, Department of Pediatrics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    3. Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota
    • Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905
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  • Communicated by Claude Férec

Abstract

Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (<1.0%) and two SUDS cases (1.6%) harbored potentially pathogenic mutations in KCND3. The novel p.Val392Ile, p.Ser530Pro, and p.Gly600Arg mutations involved highly conserved residues and were absent in 1,560 reference alleles. Although the SIDS-associated p.Ser530Pro mutation demonstrated a wild-type (WT) electrophysiological phenotype when heterologously expressed, the SUDS-associated p.Val392Ile and p.Gly600Arg mutations significantly increased peak current density at +40 mV in comparison with WT by 100.4% (P < 0.05) and 50.4% (P < 0.05), respectively. p.Val392Ile also slowed recovery from inactivation 3.6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. Hum Mutat 33:989–997, 2012. © 2012 Wiley Periodicals, Inc.

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