These authors contributed equally to the research and are joint first authors.
Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death†
Article first published online: 27 MAR 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on CNV Detection with Diagnostic Arrays
Volume 33, Issue 6, pages 989–997, June 2012
How to Cite
Giudicessi, J. R., Ye, D., Kritzberger, C. J., Nesterenko, V. V., Tester, D. J., Antzelevitch, C. and Ackerman, M. J. (2012), Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Hum. Mutat., 33: 989–997. doi: 10.1002/humu.22058
Communicated by Claude Férec
- Issue published online: 7 MAY 2012
- Article first published online: 27 MAR 2012
- Accepted manuscript online: 21 FEB 2012 12:17PM EST
- Manuscript Accepted: 7 FEB 2012
- Manuscript Received: 21 NOV 2011
- Windland Smith Rice Comprehensive Sudden Cardiac Death Program (M.J.A.); the Dr. Scholl Foundation (M.J.A.); Hannah Wernke Memorial Foundation (M.J.A.); and the National Institutes of Health (R01-HD42569 to M.J.A., R01-HL47678 to C.A., and F30-HL106993 to J.R.G.)
- sudden death;
- ion channels;
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.