Infant Sudden Death: Novel Mutations Responsible for Impaired Nav1.5 Channel Function

Abstract

Sudden infant death syndrome (SIDS) is the leading cause of mortality in apparently normal infants. During 2008 to 2012, the New York City Office of Chief Medical Examiner (OCME) examined 274 cases of sudden unexplained death (SUD) of which 141 were infants below 1 year of age, with ∼93% of these less than 6 months of age at the time of death. Several ion channelopathies were found during genetic screening. An African-American/Hispanic girl who died suddenly in her sleep at the age of 5 weeks carried two SCN5A mutations: c.5494 C>G and c.5830 C>T, which respectively introduces a missense mutation Q1832E and an early stop codon R1944X in the distal C-terminus of the cardiac Na+ channel -subunit, Nav1.5. HEK-293 cells were transfected with cDNAs of wild-type Nav1.5, Nav1.5-Q1832E, Nav1.5Δ1944 (the C-terminal truncation) or a cDNA with both mutations (Nav1.5-Q1832E-Δ1944) and were subjected to whole-cell patch clamping. The peak Nav1.5-Q1832E current was reduced by almost 10-fold (e.g. at −20mV the wild-type Nav1.5 was 283±49.1 pA/pF, n=8 cf. −31±11.8 pA/pF, n=4, for Nav1.5-Q1832E, p<0.001), whereas Nav1.5Δ1944 and Nav1.5-Q1832E-Δ1944 currents were not significantly different from wild-type. The inactivation time constants were unaffected by any of the mutations (e.g. at −10mV, 1 and 2 respectively were 1.3±0.15 and 7.7±0.87 ms, n=8 for wild-type cf. 1.1±0.21 and 7.5±1.61 ms, n=4, for Nav1.5-Q1832E). No significant differences were observed for the time course of the recovery from inactivation or the voltage dependence of the activation and inactivation kinetic variables. Preliminary biotinylation experiments suggest that the Nav1.5-Q1832E surface expression was unaltered compared to wild-type, suggesting a defect independent of trafficking. In conclusion, the Q1832E mutation was sufficient to produce a severely dysfunctional Nav1.5 channel, which may have been contributing to the victim's sudden death.