Biology subjects

Rabkina, I.

Publications and source records attributed to Rabkina, I..

3 recordsLinked to original sources

bioRxiv2022

Deficiency of Heterogeneous Nuclear Ribonucleoprotein U leads to delayed neurogenesis

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level. HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors in the maturing neuronal population. We conclude that, HNRNPU locus is involved in delayed commitment of neural progenitors to neuronal maturation in cell types with hindbrain profile.

neuroscience↗

bioRxiv2019

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

CASK-related disorders are a genetically defined group of neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders. HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels

genetics↗

bioRxiv2018

Association Between Rare Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder

Challenges in social communication and interaction are core symptoms in autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest but heterogeneous effects in clinical trials, and therefore identification of effect moderators could enable more precise intervention decisions. One of the major genetic risk factors in ASD are rare copy number variation (CNV). However, limited information exists whether rare CNVs profiles can be used to aid in intervention decisions. Therefore, we conducted the first study to date analyzing rare CNVs as genetic moderators in the outcome of SSGT in ASD. For this, we analyzed rare genic CNV carrier status of 207 children of which 105 received SSGT and 102 standard care as part of a recent randomized clinical trial for 12-weeks SSGT. We used mixed linear models to assess the association of being a CNV carrier, grouped by the effect and size of the CNVs and the primary response to SSGT, the parent-report Social Responsiveness Scale (SRS) measured at post-intervention and 3-months follow-up. Additionally, we analyzed the secondary outcome assessments included parent-rated adaptive behaviors (ABAS-II) and trainer-rated clinical global impression (CGI). We show that being a carrier of any size rare genic CNV did not impact on the SSGT outcome. However, when stratifying the groups by size of the CNVs, we identified that carriers of large CNVs (>500 kb) showed inferior SRS outcomes at post-intervention ({beta} = 15.35, 95% CI 2.86-27.84, P=0.017) and follow-up ({beta} = 14.19, 95% CI 1.68-26.70, P=0.028). Similar results were shown for the parent-rated secondary outcome. In contrast, the carriers of small CNVs had better outcome at post-intervention ({beta} = -1.20, 95 % CI - 2.0 - -0.4 P = 0.003) but not at follow-up for the trainer-rated secondary outcome CGI. These results remained when we tested the specificity of the effect by including the standard care group and adjusting for IQ levels. While our study suggests that being a carrier of any size rare genic CNV did not impact the outcome, it provides preliminary evidence that carriers of high-risk CNVs might not benefit on SSGT as much as non-carriers. Our results indicate that genetic information eventually might help guide personalized intervention planning in ASD. We additionally highlight that more research is needed to understand the intervention needs of autistic individuals with specified molecular alterations.

genetics↗