Rare pathogenic variants in WNK3 cause X-linked intellectual disability

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS

Experimental study of fast electron propagation in compressed matter

We report on experimental results of the fast electron transport in compressed plasmas, created by laser-induced shock propagation in both cylindrical and planar geometry. Two experiments were carried out. The first one was based on the compression of a polyimide cylinder filled with foams of three different initial densities (rho(0)). X-ray and proton radiographies of the target during the compression coupled with hydrodynamic simulations show that the obtained core densities and temperatures range from 2 to 11 g/cm(3) and from 30 to 120 eV, respectively. By studying the K-shell fluorescence from dopant atoms inside the target and from tracer layers situated at both front and rear side of the target it has been possible to investigate the fast electron propagation. The results show that Cu K-alpha yield emitted by the target rear side foil decreases with increasing compression, independently of rho(0). An electron collimation can also be observed for certain experimental conditions where a convergent resistivity gradient interacts with the fast electron beam. The second experiment was performed in a planar geometry with a compressing shock counter-propagative to the fast electron beam. In this case the areal density rho z seen by the electrons is constant during the compression in such a way that changes in the fast electron range should be ascribed to collective mechanisms. The study of the K-alpha fluorescence, from buried fluorescent layers of different atomic numbers, shows that the electrons with energy <75 key are more affected by resistive losses in compressed compared to non-compressed targets. These two experiments were part of the Experimental Fusion Validation Program of the HiPER project