Thrombotic antiphospholipid syndrome (TAPS) is an autoimmune disorder that manifests with venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) in the presence of persistent antiphospholipid antibodies (aPLs). Recent trials have failed to demonstrate non-inferiority of the direct oral anticoagulants (DOACs) compared to vitamin K antagonists as anticoagulation in TAPS, but there is a subgroup of non-triple positive patients without prior ATE in who only limited data exists. The objective of this study was to assess the effectiveness and safety of DOACs in non-triple positive TAPS without prior ATE.
View Article and Find Full Text PDFDIX-domain containing 1 (Dixdc1) is an important regulator of neuronal development including cortical neurogenesis, neuronal migration and synaptic connectivity, and sequence variants in the gene have been linked to autism spectrum disorders (ASDs). Previous studies indicate that Dixdc1 controls neurogenesis through Wnt signaling, whereas its regulation of dendrite and synapse development requires Wnt and cytoskeletal signaling. However, the prediction of these signaling pathways is primarily based on the structure of Dixdc1.
View Article and Find Full Text PDFUnlabelled: Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, 'isogenic' iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD.
View Article and Find Full Text PDFAutism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable.
View Article and Find Full Text PDFThe huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington's disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence.
View Article and Find Full Text PDFAtypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown.
View Article and Find Full Text PDFCopy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.
View Article and Find Full Text PDFJ Neurodev Disord
December 2016
Background: Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.
View Article and Find Full Text PDFCortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth.
View Article and Find Full Text PDFThe development of neural connectivity is essential for brain function, and disruption of this process is associated with autism spectrum disorders (ASDs). DIX domain containing 1 (DIXDC1) has previously been implicated in neurodevelopmental disorders, but its role in postnatal brain function remains unknown. Using a knockout mouse model, we determined that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex.
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