Bundgaardmathews4997
A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.
We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.
Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.
Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines.
We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known developmental disorder genes using exome sequence data from the Deciphering Developmental Disorders (DDD) study.
Of these ClinVar pathogenic variants, 3.6% were identified among 13,462 DDD probands, and 1134/1352 (83.9%) had already been independently communicated to clinicians using DDD variant filtering pipelines as plausibly pathogenic. The remaining 218 variants failed consequence, inheritance, or other automated variant filters. Following clinical review of these additional variants, we were able to identify 112 variants in 107 (0.8%) DDD probands as potential diagnoses.
Lower minor allele frequency (<0.0005%) and higher gold star review status in ClinVar (>1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.
1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The stringent response is a stress signalling system mediated by the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) in response to nutrient deprivation. Recent research highlights the complexity and broad range of functions that these alarmones control. This Review provides an update on our current understanding of the enzymes involved in ppGpp, pppGpp and guanosine 5'-monophosphate 3'-diphosphate (pGpp) (collectively (pp)pGpp) turnover, including those shown to produce pGpp and its analogue (pp)pApp. We describe the well-known interactions with RNA polymerase as well as a broader range of cellular target pathways controlled by (pp)pGpp, including DNA replication, transcription, nucleotide synthesis, ribosome biogenesis and function, as well as lipid metabolism. TP-0903 Finally, we review the role of ppGpp and pppGpp in bacterial pathogenesis, providing examples of how these nucleotides are involved in regulating many aspects of virulence and chronic infection.Polychlorinated biphenyls (PCBs) are ubiquitous, persistent, organic pollutants also considered endocrine-disrupting chemicals. link2 Our study examined the effects of lactational exposure to nondioxin-like PCB-155 and/or dioxin-like PCB-169 on longitudinal femur growth at the distal epiphyseal growth plate (EGP) in young rats at three different ages [postnatal days (PNDs) 9, 22, and 42]. After delivery, lactating rats were divided into four groups (PCB-169, PCB-155, PCB-155 + 169, and control) and administered PCBs intraperitoneally. The femurs of offspring were used to estimate growth rate (µm/day), and histomorphometric analysis on the distal femur included the thickness of the EGP and zones of proliferation and hypertrophy with calcification. Stereometry was used to determine trabecular bone volume density. In the PCB-169 and PCB-155 + 169 groups, PCB-169 affected longitudinal bone growth in the early postnatal period by interfering with chondrocytes in the EGP zone of proliferation and, to a lesser extent, the zone of hypertrophy. Morphometric alterations in EGP structure diminished until puberty. A slow growth rate persisted in the PCB-169 group until PND 42, while in the PCB-155 group, a fast growth rate between PNDs 9 to 22 was significantly reduced between PNDs 22 to 42. Sterometric assessment showed decreased trabecular bone volume in the PCB-155 + 169 group compared with that in the control on PND 9 and increased in the PCB-169 group compared with that in the PCB-155 group on PND 42. To summarize, studied PCB congeners exerted congener- and age-dependent effects on femur growth rate and its histomorphometric characteristics.Interferometry-based online partial discharge (PD) monitor presented in this paper can detect the occurrence of PD sensitively, evaluate the peak value of the discharge inception voltage with random waveform and the damage extent relatively cost effectively. The interferograms affected by the PD are collected online. By extracting the phase information of the interference fringes quantitatively, the peak value of the discharge inception voltage with random waveform can be retrieved real-time. Merits of the proposed method as an online quantitative PD monitor are validated via theoretical analysis as well as experimentations by the use of an artificially localized PD source. Furthermore, the proposed method can capture the light signal emitted by the discharge. Quite in contrast to many commonly used sensor-based methods, our approach avoids the need of amplifying the light signal strength making its practical implantation much convenient. The proposed method promises strong potential for field application.In recent years, the increase in blood pressure at high altitudes has become an interesting topic among high-altitude researchers. In our animal studies using Wistar rats, we observed the existence of two rat populations that exhibit differential physiological responses during hypoxic exposure. link3 These rats were classified as hypoxia-induced hypertensive rats and nonhypertensive rats. A decrease in nitric oxide levels was reported in different hypertension models associated with increased concentrations of asymmetric dimethylarginine (ADMA) and homocysteine, and we recently described an increase in arginase type II expression under hypoxia. ADMA and homocysteine decrease nitric oxide (NO) bioavailability; however, whether ADMA and homocysteine have a regulatory effect on arginase activity and therefore regulate another NO synthesis pathway is unknown. Therefore, the aim of this study was to measure basal ADMA and homocysteine levels in hypoxia-induced hypertensive rats and evaluate their effect on arginase II activity. Our results indicate that hypoxia-induced hypertensive rats presented lower nitric oxide concentrations than nonhypertensive rats, associated with higher concentrations of homocysteine and ADMA. Hypoxia-induced hypertensive rats also presented lower dimethylarginine dimethylaminohydrolase-2 and cystathionine β-synthase levels, which could explain the high ADMA and homocysteine levels. In addition, we observed that both homocysteine and ADMA had a significant effect on arginase II activation in the hypertensive rats. Therefore, we suggest that ADMA and homocysteine have dual regulatory effects on NO synthesis. The former has an inhibitory effect on eNOS, and the latter has a secondary activating effect on arginase II. We propose that arginase II is activated by AMDA and homocysteine in hypoxia-induced hypertensive rats.An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.RNA-binding proteins (RBPs) play a crucial role in cellular physiology by regulating RNA processing, translation, and turnover. In neoplasms, RBP support of cancer-relevant expression of alternatively spliced, modified, and stabilized mRNA transcripts is essential to self-renewal, proliferation, and adaptation to stress. In this review, we assess the impact of key families of RBPs in leukemogenesis, review progress in targeting those proteins with small molecules, and discuss how multilevel composition of posttranscriptional regulation of gene expression could be used for potential therapies in acute and chronic leukemia.Confined within the cold-stable Southern Ocean, Antarctic notothenioid fishes have undergone an evolutionary loss of the inducible heat shock response (HSR), while facing perpetual low-temperature challenges to cellular proteostasis. This study examines how evolution in chronic cold has affected the shared cellular apparatus that mediates proteostasis under normal and heat stressed states. To deduce Antarctic-specific changes, we compared native expression levels across the full suite of chaperome genes and assessed the structural integrity of two crucial HSR regulators - Heat Shock Factor 1 (HSF1) that activates HSR, and heat shock elements (HSEs), the binding sites for HSF1 - between Antarctic fishes and the basal temperate notothenioid Eleginops maclovinus. Native expression levels of Antarctic fish chaperomes showed very modest changes overall, contrary to the common view of constitutive upregulation in the cold. Only a few cytosolic HSP70 genes showed greater transcription, with only the ancestrally-inducible HSPA6 strongly upregulated across all Antarctic species.
