Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

Mitochondrial Ca(2+) uptake has key roles in cell life and death. Physiological Ca(2+) signaling regulates aerobic metabolism, whereas pathological Ca(2+) overload triggers cell death. Mitochondrial Ca(2+) uptake is mediated by the Ca(2+) uniporter complex in the inner mitochondrial membrane, which comprises MCU, a Ca(2+)-selective ion channel, and its regulator, MICU1. Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced. Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented. Whereas the pathophysiology of muscular dystrophy and the core myopathies involves abnormal mitochondrial Ca(2+) handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca(2+) signaling, demonstrating the crucial role of mitochondrial Ca(2+) uptake in humans.

BackgroundGenetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain.ResultsWe performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism.ConclusionsWe have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1567-1) contains supplementary material, which is available to authorized users.

The X-linked gene filamin A (Flna) encodes a widely expressed actin-binding protein that crosslinks actin into orthogonal networks and interacts with a variety of other proteins including membrane proteins, integrins, transmembrane receptor complexes and second messengers, thus forming an important intracellular signalling scaffold. Heterozygous loss of function of human FLNA causes periventricular nodular heterotopia in females and is generally lethal (cause unknown) in hemizygous males. Missense FLNA mutations underlie a spectrum of disorders affecting both sexes that feature skeletal dysplasia accompanied by a variety of other abnormalities. Dilp2 is an X-linked male-lethal mouse mutation that was induced by N-ethyl-N-nitrosourea. We report here that Dilp2 is caused by a T-to-A transversion that converts a tyrosine codon to a stop codon in the Flna gene (Y2388X), leading to absence of the Flna protein and male lethality because of incomplete septation of the outflow tract of the heart, which produces common arterial trunk. A proportion of both male and female mutant mice have other cardiac defects including ventricular septal defect. In addition, mutant males have midline fusion defects manifesting as sternum and palate abnormalities. Carrier females exhibit milder sternum and palate defects and misshapen pupils. These results define crucial roles for Flna in development, demonstrate that X-linked male lethal mutations can be recovered from ENU mutagenesis screens and suggest possible explanations for lethality of human males hemizygous for null alleles of FLNA.

Antisocial individuals have problems recognizing negative emotions (e.g. Marsh & Blair in Neuroscience and Biobehavioral Reviews 32:454–465, 2009); however, due to issues with sampling and different methods used, previous findings have been varied. Sixty-three male young offenders and 37 age-, IQ- and socio-economic status-matched male controls completed a facial emotion recognition task, which measures recognition of happiness, sadness, fear, anger, disgust, and surprise and neutral expressions across 4 emotional intensities. Conduct disorder (YSR), and psychopathic and callous/unemotional traits (YPI) were measured, and offenders’ offense data were taken from the Youth Offending Service’s case files. Relative to controls, offenders were significantly worse at identifying sadness, low intensity disgust and high intensity fear. A significant interaction for anger was also observed, with offenders showing reduced low- but increased high-intensity anger recognition in comparison with controls. Within the young offenders levels of conduct disorder and psychopathic traits explained variation in sadness and disgust recognition, whereas offense severity explained variation in anger recognition. These results suggest that antisocial youths show specific problems in recognizing negative emotions and support the use of targeted emotion recognition interventions for problematic behavior.

Data availability De novo variants discovered from the new trios are published in Supplementary Table S12. The data that support the findings of this study are available from the corresponding author upon request. Code availability A description of the R functions used for statistical analysis can be found in the Life Sciences Reporting Summary. Author contributions MCOD, MJO, JTRW, PH and ER conceived and designed the research. ER analysed the data. JH, JM and NC performed and managed the sequencing experiments. JH and MD performed the Sanger sequencing validation experiment. VEP, AJP, LH, SEL, AFP and ALR contributed to the interpretation of the results.

Objective-To test the hypothesis that treatment with bromocriptine would ameliorate deficits in clinical motivation, responsiveness to reward, and frontal cognitive function after brain injury.Method-An open trial in six men and five women who had had either traumatic brain injury or subarachnoid haemorrhage between two months and five years previously. After repeated baseline assessments, bromocriptine was given in gradually increasing doses. Assessments were repeated at increasing doses, during maintenance, and after withdrawal. Novel structured instruments for quantifying motivation were developed; measures of anxiety and depression, and cognitive tests sensitive to motivation or frontal lobe involvement were also given. Results-Bromocriptine treatment was followed by improved scores on all measures other than mood. Improvement was maintained after bromocriptine withdrawal in eight of the patients. Conclusion-Poor motivation in patients with brain injury may result from dysfunction in the mesolimbic/mesocortical dopaminergic circuitry, giving rise to associated deficiencies in reward responsiveness and frontal cognitive function.

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.