An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex

Are the Norwegian health research investments in line with the disease burden?

Background The relationship between research funding across therapeutic areas and the burden of disease in Norway has not been investigated. Further, few studies have looked at the association between national research investments and the global disease burden. The aim of the present study was to analyze the correlation between a significant part of Norwegian investment in health research and the burden of disease across therapeutic areas, using both Norwegian and global burden of disease estimates. Methods We used research investment records for 2012 from the Research Council of Norway, and the investment records distributed through liaison committees between regional health authorities and universities. Both were classified by the Health Research Classification System (HRCS). Furthermore, we used the years of life lost and Disability Adjusted Life Years (DALYs) for Norway and globally from the Global Burden of Disease 2010 project. We created a matrix to match the expenditures by HRCS with the values from the Global Burden of Disease project. Results Disease-specific research funding increased with the Norwegian burden of disease measured as years of life lost (correlation coefficient?=?0.73). Similar findings were done when the Norwegian disease burden was measured as DALYs (correlation coefficient?=?0.62). The correlation between research funding and the global disease burden was low both when years of life lost (correlation coefficient?=?0.11) and DALYs (correlation coefficient?=?0.12) were used. Generally, when the disease burden was relatively high in Norway compared with the rest of the world, research investments were also high. Conclusions Across therapeutic areas, the Norwegian research investments appeared aligned with the Norwegian disease burden. The correlation between the Norwegian research investments and the global disease burden was much lower

SLC9A6 Mutations Cause X-Linked Mental Retardation, Microcephaly, Epilepsy, and Ataxia, a Phenotype Mimicking Angelman Syndrome

Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na+/H+ exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations