BC1-FMRP interaction is modulated by 2′-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses

The brain cytoplasmic RNA, BC1, is a small non-coding RNA that is found in different RNP particles, some of which are involved in translational control. One component of BC1-containing RNP complexes is the fragile X mental retardation protein (FMRP) that is implicated in translational repression. Peptide mapping and computational simulations show that the tudor domain of FMRP makes specific contacts to BC1 RNA. Endogenous BC1 RNA is 2′-O-methylated in nucleotides that contact the FMRP interface, and methylation can affect this interaction. In the cell body BC1 2′-O-methylations are present in both the nucleus and the cytoplasm, but they are virtually absent at synapses where the FMRP–BC1–mRNA complex exerts its function. These results strongly suggest that subcellular region-specific modifications of BC1 affect the binding to FMRP and the interaction with its mRNA targets. We finally show that BC1 RNA has an important role in translation of certain mRNAs associated to FMRP. All together these findings provide further insights into the translational regulation by the FMRP–BC1 complex at synapses

Seismic signal detection by fractal dimension analysis

We introduce a new detection algorithm with improved local and regional seismic signal recognition. The method is based on the difference between seismic signals and background random noise in terms of fractal dimension D. We compare the new method extensively with standard methods currently in use at the Seismic Network of the lstituto Nazionale di Geofisica. Results from the comparisons show that the new method recognizes seismic phases detected by existing procedures, and in addition, it features a greater sensitivity to smaller signals, without an increase in the number of false alarms. The new method was tested on real continuous data and artificially simulated high-noise conditions and demonstrated a capability to recognize seismic signals in the presence of high noise. The efficiency of the method is due to a radically different approach to the topic, in that the assertion that a signal is fractal implies a relationship between the spectral amplitude of different frequencies. This relationship allows, for the fractal detector, a complete analysis of the entire frequency range under consideration.Published970-9776T. Variazioni delle caratteristiche crostali e precursoriJCR Journa

Is mechanical thrombectomy or thrombolysis universally cost-effective? A systematic review of the literature

Background: Thrombolysis (rTPA) and mechanical thrombectomy (MT) are cost-effective treatments for ischemic stroke. However, little is known about the impact of different types of health systems (HSs) on the outcome and cost of ischemic stroke. Methods: Literature search was performed on PubMed/OVID for studies without time limits. The year of publication, type of HS, cost of intervention treatment (rTPA/MT), cost of control strategy (conservative treatment or rTPA), quality-adjusted life years (QALYs) gained, and percentage of gross domestic product spent on health were recorded. The inclusion criteria were English literature, cost-effectiveness, and cost-utility analyses. The exclusion criterion was the absence of geographic coherence between the derived QALYs and the costs. The costs were inflated to 2021 and then converted to US dollar/euro. An analysis of variance or Kruskal-Wallis test was used to compare the percentage of cost reduction and the QALYs gained. Gross domestic product percentage was correlated with the QALYs gained. Results: Thirty-five studies were analyzed. No significant differences in the percentage of cost reduction were found among the different types of HS (Beveridge -14.74% [95% confidence interval {CI} -57.94/53.08] vs. Bismarck -2.27% [95% CI -122.73/118.18] vs. national insurance -0.015% [95% CI -16.96/51.00] vs. private insurance -4.05% [95% CI -32.62/13.18]). No differences were found in QALYs gained among the different HS (Beveridge 1021 [95% CI -36.37/1705.04] vs. Bismarck 440 [95% CI -2290.68/3870.68] vs. national insurance 643 [95% CI -137.54/2366.21] vs. private insurance 550 [95% CI 131.54/1128.06]). No differences were found among the QALYs gained between rTPA/conservative treatment versus rTPA/MT and rtPA + MT/MT. The percentage of gross domestic product spent on health did not correlate with the QALYs gained (rho = -0.16; P = 0.56). Conclusions: MT and rTPA are independently cost-effective among different HS

A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability

Fragile X syndrome ( FXS) results from the loss of the fragile X mental retardation protein ( FMRP), an RNA- binding protein that regulates a variety of cytoplasmic mRNAs. FMRP regulates mRNA translation and may be important in mRNA localization to dendrites. We report a third cytoplasmic regulatory function for FMRP: control of mRNA stability. In mice, we found that FMRP binds, in vivo, the mRNA encoding PSD- 95, a key molecule that regulates neuronal synaptic signaling and learning. This interaction occurs through the 3' untranslated region of the PSD- 95 ( also known as Dlg4) mRNA, increasing message stability. Moreover, stabilization is further increased by mGluR activation. Although we also found that the PSD- 95 mRNA is synaptically localized in vivo, localization occurs independently of FMRP. Through our functional analysis of this FMRP target we provide evidence that dysregulation of mRNA stability may contribute to the cognitive impairments in individuals with FXS.status: publishe

Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review

De novo variants in the WDR26 gene leading to haploinsufficiency have recently been associated with Skraban-Deardorff syndrome. This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs, including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies. Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available. Here, we describe a child with Skraban-Deardorff syndrome associated with the WDR26 pathogenic de novo variant NM_025160.6:c.69dupC, p.(Gly24ArgfsTer48), and an adult associated with the pathogenic de novo variant c.1076G > A, p.(Trp359Ter). The adult patient was a 29-year-old female with detailed information on clinical history and pharmacological treatments since birth, providing an opportunity to map disease progression and patient management. By comparing our cases with published reports of Skraban-Deardorff syndrome, we provide a genetic and clinical summary of this ultrarare condition, describe the clinical management from childhood to adult age, and further expand on the clinical phenotype

Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. Introduction: The Tousled-like kinases 1 and 2 (TLK1 and TLK2) are involved in many fundamental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with âMental Retardation Autosomal Dominant 57' (MRD57, MIM# 618050), a neurodevelopmental disorder characterised by a highly variable phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies. Methods: We re-evaluate whole exome sequencing and array-CGH data from a large cohort of patients affected by neurodevelopmental disorders. Using spatial proteomics (BioID) and single-cell gel electrophoresis, we investigated the proximity interaction landscape of TLK2 and analysed the effects of p.(Asp551Gly) and a previously reported missense variant (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localisation and activity. Results: We identified three new unrelated MRD57 families. Two were sporadic and caused by a missense change (c.1652A>G; p.(Asp551Gly)) or a 39 kb deletion encompassing TLK2, and one was familial with three affected siblings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). The clinical phenotypes were consistent with those of previously reported cases. The tested mutations strongly impaired TLK2 kinase activity. Proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4 and NACC1, were identified. Finally, we demonstrated a more relaxed chromatin state in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared with control cells, conferring susceptibility to DNA damage. Conclusion: Our study identified novel TLK2 pathogenic variants, confirming and further expanding the MRD57-related phenotype. The molecular characterisation of missense variants increases our knowledge about TLK2 function and provides new insights into its role in neurodevelopmental disorders

The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP

Strong evidence indicates that regulated mRNA translation in neuronal dendrites underlies synaptic plasticity and brain development. The fragile X mental retardation protein (FMRP) is involved in this process; here, we show that it acts by inhibiting translation initiation. A binding partner of FMRP, CYFIP1/Sra1, directly binds the translation initiation factor eIF4E through a domain that is structurally related to those present in 4E-BP translational inhibitors. Brain cytoplasmic RNA 1 (BC1), another FMRP binding partner, increases the affinity of FMRP for the CYFIP1-eIF4E complex in the brain. Levels of proteins encoded by known FMRP target mRNAs are increased upon reduction of CYFIP1 in neurons. Translational repression is regulated in an activity-dependent manner because BDNF or DHPG stimulation of neurons causes CYFIP1 to dissociate from eIF4E at synapses, thereby resulting in protein synthesis. Thus, the translational repression activity of FMRP in the brain is mediated, at least in part, by CYFIP1.status: publishe

CNVs analysis in a cohort of isolated and syndromic DD/ID reveals novel genomic disorders, position effects and candidate disease genes

Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect Copy Number Variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries likely affecting the regulatory landscape. In conclusion, we show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects