A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice

Background: Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. Methodology/Principal Findings: We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 39 UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 39 UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J

Mitochondrial 2,4-dienoyl-CoA Reductase Deficiency in Mice Results in Severe Hypoglycemia with Stress Intolerance and Unimpaired Ketogenesis

The mitochondrial β-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial β-oxidation of unsaturated fatty acids, we created a DECR–deficient mouse line. In Decr−/− mice, the mitochondrial β-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr−/− mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C18:2), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr−/− mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal β-oxidation and microsomal ω-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1α and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state

The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation.

SNAREs provide energy and specificity to membrane fusion events. Fusogenic trans-SNARE complexes are assembled from glutamine-contributing SNAREs (Q-SNAREs) embedded in one membrane and an arginine-contributing SNARE (R-SNARE) embedded in the other. Regulation of membrane fusion events is crucial for intracellular trafficking. We identify the endosomal protein Varp as an R-SNARE-binding regulator of SNARE complex formation. Varp colocalizes with and binds to VAMP7, an R-SNARE that is involved in both endocytic and secretory pathways. We present the structure of the second ankyrin repeat domain of mammalian Varp in complex with the cytosolic portion of VAMP7. The VAMP7-SNARE motif is trapped between Varp and the VAMP7 longin domain, and hence Varp kinetically inhibits the ability of VAMP7 to form SNARE complexes. This inhibition will be increased when Varp can also bind to other proteins present on the same membrane as VAMP7, such as Rab32-GTP

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val(158)Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

Globally significant greenhouse-gas emissions from African inland waters

Carbon dioxide emissions to the atmosphere from inland waters-streams, rivers, lakes and reservoirs-are nearly equivalent to ocean and land sinks globally. Inland waters can be an important source of methane and nitrous oxide emissions as well, but emissions are poorly quantified, especially in Africa. Here we report dissolved carbon dioxide, methane and nitrous oxide concentrations from 12 rivers in sub-Saharan Africa, including seasonally resolved sampling at 39 sites, acquired between 2006 and 2014. Fluxes were calculated from published gas transfer velocities, and upscaled to the area of all sub-Saharan African rivers using available spatial data sets. Carbon dioxide-equivalent emissions from river channels alone were about 0.4 Pg carbon per year, equivalent to two-thirds of the overall net carbon land sink previously reported for Africa. Including emissions from wetlands of the Congo river increases the total carbon dioxide-equivalent greenhouse-gas emissions to about 0.9 Pg carbon per year, equivalent to about one quarter of the global ocean and terrestrial combined carbon sink. Riverine carbon dioxide and methane emissions increase with wetland extent and upland biomass. We therefore suggest that future changes in wetland and upland cover could strongly affect greenhouse-gas emissions from African inland waters