A common mechanism of defective channel trafficking underlying DFNA2 hearing loss result in different cell surface expression levels of KCNQ4 mutants

KCNQ4 mutations underlie DFNA2, a subtype of autosomal dominant hearing loss. We had previously identified the pore-region p.G296S mutation that impaired channel activity in two manners: it greatly reduced surface expression and abolished channel function. Moreover, G296S mutant exerted a strong dominant-negative effect on potassium currents by reducing the channel expression at the cell surface representing the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2. Here, we have investigated the pathogenic mechanism associated with all the described KCNQ4 mutations (F182L, W242X, E260K, D262V, L274H, W276S, L281S, G285C, G285S and G321S) that are located in different domains of the channel protein. F182L mutant showed a wild type-like cell-surface distribution in transiently transfected NIH3T3 fibroblasts and the recorded currents in Xenopus oocytes resembled those of the wild-type. The remaining KCNQ4 mutants abolished potassium currents, but displayed distinct levels of defective cell-surface expression in NIH3T3 as quantified by flow citometry. Co-localization studies revealed these mutants were retained in the ER, unless W242X, which showed a clear co-localization with Golgi apparatus. Interestingly, this mutation results in a truncated KCNQ4 protein at the S5 transmembrane domain, before the pore region, that escapes the protein quality control in the ER but does not reach the cell surface at normal levels. Currently we are investigating the trafficking behaviour and electrophysiological properties of several KCNQ4 truncated proteins artificially generated in order to identify specific motifs involved in channel retention/exportation. Altogether, our results indicate that a defect in KCNQ4 trafficking is the common mechanism underlying DFNA2

Sensitivity of a distributed temperature-radiation index melt model based on AWS observations and surface energy balance fluxes, Hurd Peninsula glaciers, Livingston Island, Antarctica

We use an automatic weather station and surface mass balance dataset spanning four melt seasons collected on Hurd Peninsula Glaciers, South Shetland Islands, to investigate the point surface energy balance, to determine the absolute and relative contribution of the various energy fluxes acting on the glacier surface and to estimate the sensitivity of melt to ambient temperature changes. Long-wave incoming radiation is the main energy source for melt, while short-wave radiation is the most important flux controlling the variation of both seasonal and daily mean surface energy balance. Short-wave and long-wave radiation fluxes do, in general, balance each other, resulting in a high correspondence between daily mean net radiation flux and available melt energy flux. We calibrate a distributed melt model driven by air temperature and an expression for the incoming short-wave radiation. The model is calibrated with the data from one of the melt seasons and validated with the data of the three remaining seasons. The model results deviate at most 140 mm w.e. from the corresponding observations using the glaciological method. The model is very sensitive to changes in ambient temperature: a 0.5 ◦ C increase results in 56 % higher melt rates.