A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia.

OBJECTIVES Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance. METHODS AND RESULTS A 12-year-old male with congenital sick sinus syndrome (SSS), cardiac conduction disorder (CCD), and recurrent monomorphic ventricular tachycardia (VT) had mutational analysis that identified a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of SCN5A. The mutation was also present in six asymptomatic family members only two of which showed mild ECG phenotypes. The deletion caused a frame-shift mutation (L1821fs/10) with truncation of the C-terminus after 10 missense amino acid substitutions. When expressed in HEK-293 cells for patch-clamp study, the current density of L1821fs/10 was reduced by 90% compared with WT. In addition, gating kinetic analysis showed a 5-mV positive shift in activation, a 12-mV negative shift of inactivation and enhanced intermediate inactivation, all of which would tend to reduce peak and early sodium current. Late sodium current, however, was increased in the mutated channels. CONCLUSIONS The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.

Reconstructing the subsurface ocean decadal variability using surface nudging in a perfect model framework

Initialising the ocean internal variability for decadal predictability studies is a new area of research and a variety of ad hoc methods are currently proposed. In this study, we explore how nudging with sea surface temperature (SST) and salinity (SSS) can reconstruct the threedimensional variability of the ocean in a perfect model framework. This approach builds on the hypothesis that oceanic processes themselves will transport the surface information into the ocean interior as seen in ocean-only simulations. Five nudged simulations are designed to reconstruct a 150 years ‘‘target’’ simulation, defined as a portion of a long control simulation. The nudged simulations differ by the variables restored to, SST or SST + SSS, and by the area where the nudging is applied. The strength of the heat flux feedback is diagnosed from observations and the restoring coefficients for SSS use the same time-scale. We observed that this choice prevents spurious convection at high latitudes and near sea-ice border when nudging both SST and SSS. In the tropics, nudging the SST is enough to reconstruct the tropical atmosphere circulation and the associated dynamical and thermodynamical impacts on the underlying ocean. In the tropical Pacific Ocean, the profiles for temperature show a significant correlation from the surface down to 2,000 m, due to dynamical adjustment of the isopycnals. At mid-tohigh latitudes, SSS nudging is required to reconstruct both the temperature and the salinity below the seasonal thermocline. This is particularly true in the North Atlantic where adding SSS nudging enables to reconstruct the deep convection regions of the target. By initiating a previously documented 20-year cycle of the model, the SST + SSS nudging is also able to reproduce most of the AMOC variations, a key source of decadal predictability. Reconstruction at depth does not significantly improve with amount of time spent nudging and the efficiency of the surface nudging rather depends on the period/events considered. The joint SST + SSS nudging applied verywhere is the most efficient approach. It ensures that the right water masses are formed at the right surface density, the subsequent circulation, subduction and deep convection further transporting them at depth. The results of this study underline the potential key role of SSS for decadal predictability and further make the case for sustained largescale observations of this field.