The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function

The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus

Screening for distant metastases in patients with ipsilateral breast tumor recurrence: the impact of different imaging modalities on distant recurrence-free interval

Purpose In patients with ipsilateral breast tumor recurrence (IBTR), the detection of distant disease determines whether the intention of the treatment is curative or palliative. Therefore, adequate preoperative staging is imperative for optimal treatment planning. The aim of this study is to evaluate the impact of conventional imaging techniques, including chest X-ray and/or CT thorax-(abdomen), liver ultrasonography(US), and skeletal scintigraphy, on the distant recurrence-free interval (DRFI) in patients with IBTR, and to compare conventional imaging with 18F-FDG PET-CT or no imaging at all. Methods This study was exclusively based on the information available at time of diagnoses of IBTR. To adjust for differences in baseline characteristics between the three imaging groups, a propensity score (PS) weighted method was used. Results Of the 495 patients included in the study, 229 (46.3%) were staged with conventional imaging, 89 patients (19.8%) were staged with 18F-FDG PET-CT, and in 168 of the patients (33.9%) no imaging was used (N=168). After a follow-up of approximately 5 years, 14.5% of all patients developed a distant recurrence as frst event after IBTR. After adjusting for the PS weights, the Cox regression analyses showed that the diferent staging methods had no signifcant impact on the DRFI. Conclusions This study showed a wide variation in the use of imaging modalities for staging IBTR patients in the Netherlands. After using PS weighting, no statistically signifcant impact of the diferent imaging modalities on DRFI was shown. Based on these results, it is not possible to recommend staging for distant metastases using 18F-FDG PET-CT over conventional imaging technique