Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.

Key Points Mutations in a conserved intronic enhancer element lead to GATA2 haploinsufficiency. Mutations in GATA2, regardless of mutation type, lead to decreased GATA2 transcript levels and a common global transcriptional profile.

Summary Vascular permeability is frequently associated with inflammation and triggered by a cohort of secreted permeability factors such as VEGF. Here we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Both global and endothelial-specific deletion of PR block physiological vascular permeability in the uterus whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with ChIP-sequencing revealed that PR induces a NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely and venous-specific regulation of vascular barrier function that is critical to embryo implantation.

Both IgCAMs and the actin cytoskeleton play critical roles in neuronal growth cone motility and guidance. However, it is unclear how IgCAM receptors transduce signals from the plasma membrane to induce actin remodeling. Previous studies have shown that local clustering and immobilization of apCAM, the Aplysia homolog of NCAM, induces Src kinase activity and F-actin polymerization in the peripheral domain of cultured Aplysia bag cell growth cones. Therefore, we wanted to test whether the Src kinase substrate and actin regulator cortactin could be a molecular link between Src activity and actin assembly during apCAM-mediated growth cone guidance. Here, we cloned Aplysia cortactin and showed that it is abundant in the nervous system. Immunostaining of growth cones revealed a strong colocalization of cortactin with F-actin in filopodial bundles and at the leading edge of lamellipodia. Perturbation of the cytoskeleton indicated that cortactin distribution largely depends on actin filaments. Furthermore, active Src colocalized with cortactin in regions of actin assembly, including leading edge and filopodia tips. Finally, we observed that cortactin, like F-actin, localizes to apCAM adhesion sites mediating growth cone guidance. Altogether, these data suggest that cortactin is a mediator of IgCAM-triggered actin assembly in the growth cone and involved in motility and guidance.

These results suggest that pediatric CVID is not a distinct phenotype. Major features were comparable across the groups. This study underscores the need for continued longitudinal study of pediatric and early-onset CVID patients to further characterize accrual of features over time.

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Background This study’s objective was to determine if parenteral cysteine when compared to isonitrogenous non-cysteine supplementation increases erythrocyte reduced glutathione (GSH) in neonates at high risk for inflammatory injury. Material and Methods Neonates with a score for neonatal acute physiology (SNAP) > 10 requiring mechanical ventilation and parenteral nutrition (PN) were randomized in a double-blinded, placebo controlled study to receive parenteral cysteine-HCl (CYS group) or additional PN amino acids (ISO group) at 121 mg/kg/day for ≥ seven days. A six-hour [13C2] glycine IV infusion was administered at study week one to determine fractional synthetic rate of glutathione (FSR-GSH). Results Baseline characteristics were similar between the CYS (n=17) and ISO groups (n=21). Erythrocyte GSH and total glutathione concentrations, GSH:oxidized glutathione (GSSG), and FSR-GSH after treatment were not different between groups. However, the CYS group had a larger individual positive change in GSH and total glutathione (infusion day – baseline) compared to the ISO group (p=0.02 for each). After adjusting for treatment, a lower enrollment weight and red blood cell (RBC) transfusion were associated with a decreased change in total glutathione and GSH (p< 0.05 for each). Conclusion When compared to isonitrogenous non-cysteine supplementation, high dose cysteine supplementation for at least one week in critically ill neonates resulted in a larger and more positive individual change in glutathione. Smaller infants and those who received transfused blood demonstrated less effective change in glutathione with cysteine supplementation. The benefit of cysteine remains promising and deserves further investigation.