title: Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.
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 (I(to) ) 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.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Giudicessi
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Kritzberger
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Nesterenko
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001344:Autopsy; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D051672:Shal Potassium Channels / Q000235:genetics* / Q000378:metabolism; D013398:Sudden Infant Death / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D051672:Shal Potassium Channels