Description: Background Retinoblastoma (Rb) is a childhood cancer of the retina, commonly initiated by biallelic inactivation of the RB1 gene. Knowledge of the presence of a heritable RB1 mutation can help in risk management and reproductive decision making. We report here on RB1 mutation scanning in a unique nationwide cohort of Rb patients from the Netherlands. Methods From the 1173 Rb patients registered in the Dutch National Retinoblastoma Register until January 2013, 529 patients from 433 unrelated families could be included. RB1 mutation scanning was performed with different detection methods, depending on the time period. Results Our mutation detection methods revealed RB1 mutations in 92% of bilateral and/or familial Rb patients and in 10% of non-familial unilateral cases. Overall an RB1 germline mutation was detected in 187 (43%) of 433 Rb families, including 33 novel mutations. The distribution of the type of mutation was 37% nonsense, 20% frameshift, 21% splice, 9% large indel, 5% missense, 7% chromosomal deletions and 1% promoter. Ten per cent of patients were mosaic for the RB1 mutation. Six three-generation families with incomplete penetrance RB1 mutations were found. We found evidence that two variants, previously described as pathogenic RB1 mutations, are likely to be neutral variants. Conclusions The frequency of the type of mutations in the RB1 gene in our unbiased national cohort is the same as the mutation spectrum described worldwide. Furthermore, our RB1 mutation detection regimen achieves a high scanning sensitivity.

Description: Shelves have been estimated to account for more than one-fifth of the global marine primary production. It has been also conjectured that shelves strongly influence the oceanic absorption of anthropogenic CO2 (carbon shelf pump). Owing to their coarse resolution, currently applied global climate models are inappropriate to investigate the impact of climate change on shelves and regional models do not account for the complex interaction with the adjacent open ocean. In this study, a global ocean general circulation model and biogeochemistry model were set up with a distorted grid providing a maximal resolution for the NW European shelf and the adjacent northeast Atlantic. Using model climate projections we found that already a~moderate warming of about 2.0 K of the sea surface is linked with a reduction by ~ 30% of the biological production on the NW European shelf. If we consider the decline of anthropogenic riverine eutrophication since the 1990s, the reduction of biological production amounts is even larger. The relative decline of NW European shelf productivity is twice as strong as the decline in the open ocean (~ 15%). The underlying mechanism is a spatially well confined stratification feedback along the continental shelf break. This feedback reduces the nutrient supply from the deep Atlantic to about 50%. In turn, the reduced productivity draws down CO2 absorption in the North Sea by ~ 34% at the end of the 21st century compared to the end of the 20th century implying a strong weakening of shelf carbon pumping. Sensitivity experiments with diagnostic tracers indicate that not more than 20% of the carbon absorbed in the North Sea contributes to the long-term carbon uptake of the world ocean. The rest remains within the ocean's mixed layer where it is exposed to the atmosphere. The predicted decline in biological productivity, and decrease of phytoplankton concentration (in the North Sea by averaged 25%) due to reduced nutrient imports from the deeper Atlantic will probably affect the local fish stock negatively and therefore fisheries in the North Sea.