Objectives In the management of two related patients with multicentric glomus jugulare tumors, given the incidence of 1:30,000 with approximately 20% familial cases, our objective was to review the genetic characteristics and inheritance patterns of these tumors and to determine what molecular genetic screening possibilities exist for the phenotypically normal family members. In addition, our aim was to review the incidence of various multicentric paraganglioma (PGL) tumor location combinations. Methods Molecular genetic linkage analysis testing was performed on the 2 patients and 14 other unaffected family members. We report the results of this screening and review the literature on the incidence and genetics of paragangliomas. Results The inheritance pattern in the literature demonstrates autosomal dominant transmission with maternal imprinting (inactivation). The proclivity for multicentric origin increases to 26% in familial cases, as reflected in our patients. In addition to the two patients, four unaffected family members demonstrated the presence of the disease haplotype at chromosome band 11q23, which indicates a very high likelihood of developing a paraganglioma, given the highly penetrant nature of the disease. Conclusions It is clear that the familial PGL gene locus is situated at chromosome 11q23. The gene itself and its exact degree of penetrance, however, still await identification. Since early detection of paragangliomas reduces the incidence of morbidity and mortality, genotypic analysis as a screening tool in families of affected patients should play a front‐line diagnostic role, leading to more timely and cost‐effective patient management.

Protein recoding by RNA editing is required for normal health and evolutionary adaptation. However, de novo induction of RNA editing in response to environmental factors is an uncommon phenomenon. While APOBEC3A edits many mRNAs in monocytes/macrophages in response to hypoxia and interferons, the physiological significance of such editing is unclear. Here we show that the related APOBEC3G cytidine deaminase induces site-specific C-to-U RNA editing in natural killer (NK), CD8+ T cells and lymphoma cell lines upon cellular crowding and hypoxia. RNASeq analysis of hypoxic NK cells reveals widespread C-to-U recoding mRNA editing that is enriched for genes involved in mRNA translation. APOBEC3G promotes Warburg-like metabolic remodeling and reduces proliferation of HuT78 T cells under similar conditions. Hypoxia-induced RNA editing by APOBEC3G can be mimicked by the inhibition of mitochondrial respiration, and occurs independently of HIF-1α. Thus, APOBEC3G is an endogenous RNA editing enzyme, which is induced by mitochondrial hypoxic stress to promote adaptation in lymphocytes.

Increased red cell distribution width (RDW), which measures erythrocyte size variability (anisocytosis), has been linked to early mortality in many diseases and normal aged population through unknown mechanisms. Hypoxia has been proposed to increase both RDW and mortality. However, experimental evidence, especially in animal models, is lacking. Here, we show that chronic hypobaric hypoxia (~10% O2) increases erythrocyte numbers, hemoglobin and RDW, while reducing longevity in male mice. Compound heterozygous knockout (chKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc and Sdhd reduce high RDW and immature reticulocyte fraction, and increase healthy lifespan in chronic hypoxia. Hemoglobin and erythrocyte numbers in hypoxia do not show statistically significant differences between Sdh chKO and WT mice. These results identify a mitochondrial mechanism regulating both RDW and organismal adaptation to chronic hypoxia, and suggest SDH as a potential therapeutic target to reduce high RDW-associated clinical mortality.