Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies

Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

Memory performance is associated with education attainment: Greater influence of education in females

<p>November is national Alzheimer's Disease awareness month. Have you ever wondered how you can help the cause? We are using crowd-sourcing to study how the brain works with a simple ten minute memory game. Come and join our scientific research study at mindcrowd.org and be part of our fight against Alzheimer's and other brain diseases. Your healthy brain can help us understand what goes wrong during disease! After you complete the test you can see your results and compare yourself against other test takers.</p> <p>This figure shows several key findings from our study thus far. The data shown here is derived from approximately 20,000 test takers of all ages. We are showing three different education levels across both genders - High School degree or less, Undergraduate college degree, and Graduate degree. Note that for each gender more education is associated with higher memory performance (y-axis is test performance with higher numbers meaning better performance). In females, this effect is much more of a step-wise effect while in males the largest improvement is realized between undergraduate and graduate attainment. Secondly you can see from the figure that education attainment doesn't protect against the effect of age in memory performance (age is on the x-axis and increases from 25-85, left to right) - all education levels demonstrate an age-related decrease in performance. Lastly, you can see that males decline much more rapidly than females. This is indicated by the steeper slope of the lines in the males. So, a simple graph that demonstrates three very interesting aspects of memory performance.</p> <p>This is an actual scientific study. Please help us keep the integrity of our work high by only taking the test once and by not posting the word pairs here in the comments section. Thanks.</p> <p>NOTE FOR THE SCIENCE GEEKS - our memory task is a verbal paired associates learning paradigm. It tests a form of memory known as episodic memory. The significance of this effect in females is p < 2.2e-16 and in males it is p = 4.283e-15. The effect size for high school versus undergraduate is -7.12% in females and -3.41% in males, for undergraduate versus graduate it is -4.85% in females and -4.41% in males. The graph was made in R/ggplot2, the lines are linear fit with 95% shaded confidence intervals. The statistical analysis was performed using a multiple linear regression model that incorporated all of our other measured demographic and lifestyle variables (approximately 25 different other co-variates).</p

Between ages 18-85, men exhibit faster reaction times to a visual stimulus. Be a part of our research study into brain function at mindcrowd.org

<p>We are interested in better understanding how the brain works and we created a web-based game at mindcrowd.org with the hopes of generating the largest ever scientific study population. This plot illustrates our reaction time data analyzed by the participant’s gender. Each small “dot” represents one individual test taker (over 30,000 of them!) and they are colored with the stereotypical colors for gender. Age in years is denoted on the x-axis and on the y-axis is the median reaction time in milliseconds. The reaction time test has very simple rules – when a figure appears on the screen each test taker is asked to hit the enter key. It directly tests the connections between the test taker’s eyes-brain-finger. This is of general interest to neuroscientists because it is a question of basic connectivity, or neuronal “wiring”, in the body. We are interested in what influences this, and many other features of our brain and nervous system. Note from the data that the genders are separated in reaction time response by an average of approximately 20 milliseconds across the entire studied age spectrum from 18-85 (the lines are the mean response time with the bordering shaded areas reflecting the 95% confidence intervals for the measurement). This suggests that the male and female “wiring system” for this particular task is different. The reason why is a topic for another discussion… in the meantime please come and spend just 10 minutes at our research study site and join the MindCrowd! Visit us at mindcrowd.org and help us spread the word via your social network. Our goal is an ambitious one – to reach 1 million test takers! Help us please!</p

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A\u3eG) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype–phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A\u3eG splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK\u27s ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.status: publishe

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies