ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuit

ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits

The solar particle event of July 16–19, 1966 and its possible association with a flare on the invisible solar hemisphere

An energetic solar proton and electron event was observed by particle detectors aboard Explorer 33 (AIMP-1) and OGO-3 during the period July 16–19, 1966. Optical and radio observations of the sun suggest that these particles were produced by a flare which may have occurred on July 16 near the central meridian of the invisible hemisphere. The active region to which the flare is assigned is known to have produced the energetic particle events of July 7 and 28 , 1966. The propagation of the particles in the July 16–19 event over the ∼180° extent of solar longitude from the flare to the earth is discussed, and it is concluded that there must exist a means of rapidly distributing energetic particles over a large area of the sun. Several possible mechanisms are suggested.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43748/1/11207_2004_Article_BF00150955.pd

DRD4 Polymorphism Moderates the Effect of Alcohol Consumption on Social Bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Forecasting Solar Energetic Particle (SEP) events with Flare X-ray peak ratios

Solar flare X-ray peak fluxes and fluences in the 0.1–0.8 nm band are often used in models to forecast solar energetic particle (SEP) events. Garcia (2004) [Forecasting methods for occurrence and magnitude of proton storms with solar soft X rays, Space Weather, 2, S02002, 2004] used ratios of the 0.05–0.4 and 0.1–0.8 nm bands of the X-ray instrument on the GOES spacecraft to plot inferred peak flare temperatures versus peak 0.1–0.8 nm fluxes for flares from 1988 to 2002. Flares associated with E > 10 MeV SEP events of >10 proton flux units (pfu) had statistically lower peak temperatures than those without SEP events and therefore offered a possible empirical forecasting tool for SEP events. We review the soft and hard X-ray flare spectral variations as SEP event forecast tools and repeat Garcia’s work for the period 1998–2016, comparing both the peak ratios and the ratios of the preceding 0.05–0.4 nm peak fluxes to the later 0.1–0.8 nm peak fluxes of flares >M3 to the occurrence of associated SEP events. We divide the events into eastern and western hemisphere sources and compare both small (1.2–10 pfu) and large (≥300 pfu) SEP events with those of >10 pfu. In the western hemisphere X-ray peak ratios are statistically lower for >10 pfu SEP events than for non-SEP events and are even lower for the large (>300 pfu) events. The small SEP events, however, are not distinguished from the non-SEP events. We discuss the possible connections between the flare X-ray peak ratios and associated coronal mass ejections that are presumed to be the sources of the SEPs