Pubmed du 19/06/20

vendredi 19 juin 2020

1. Aldinger KA, Timms AE, MacDonald JW, McNamara HK, Herstein JS, Bammler TK, Evgrafov OV, Knowles JA, Levitt P. Transcriptome data of temporal and cingulate cortex in the Rett syndrome brain. Sci Data ;2020 (Jun 19) ;7(1):192.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation in the methyl-CpG-binding protein 2 gene (MECP2) in the majority of cases. We describe an RNA sequencing dataset of postmortem brain tissue samples from four females clinically diagnosed with Rett syndrome and four age-matched female donors. The dataset contains 16 transcriptomes, including two brain regions, temporal and cingulate cortex, for each individual. We compared our dataset with published transcriptomic analyses of postmortem brain tissue from Rett syndrome and found consistent gene expression alterations among regions of the cerebral cortex. Our data provide a valuable resource to explore the biology of the human brain in Rett syndrome.

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2. Breen MS, Browne A, Hoffman GE, Stathopoulos S, Brennand K, Buxbaum JD, Drapeau E. Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism. Mol Autism ;2020 (Jun 19) ;11(1):53.

BACKGROUND : Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. METHODS : We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs ; n = 39) and induced forebrain neurons (hiPSC-neurons ; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. RESULTS : Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR < 5%). Genes under-expressed in PMS were implicated in Wnt signaling, embryonic development, and protein translation, while over-expressed genes were enriched for pre- and postsynaptic density genes, regulation of synaptic plasticity, and G-protein-gated potassium channel activity. Gene co-expression network analysis identified two modules in hiPSC-neurons that were over-expressed in PMS, implicating postsynaptic signaling and GDP binding, and both modules harbored a significant enrichment of genetic risk loci for developmental delay and intellectual disability. Finally, PMS-associated genes were integrated with other ASD hiPSC transcriptome findings and several points of convergence were identified, indicating altered Wnt signaling and extracellular matrix. LIMITATIONS : Given the rarity of the condition, we could not carry out experimental validation in independent biological samples. In addition, functional and morphological phenotypes caused by loss of SHANK3 were not characterized here. CONCLUSIONS : This is the largest human neural sample analyzed in PMS. Genome-wide RNA-sequencing in hiPSC-derived neural cells from individuals with PMS revealed both shared and distinct transcriptional signatures across hiPSC-NPCs and hiPSC-neurons, including many genes implicated in risk for ASD, as well as specific neurobiological pathways, including the Wnt pathway.

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3. Gabis LV, Attia OL, Roth-Hanania R, Foss-Feig J. Motor delay - An early and more common "red flag" in girls rather than boys with autism spectrum disorder. Res Dev Disabil ;2020 (Jun 19) ;104:103702.

BACKGROUND : Autism and intellectual disability may coincide and be preceded by global developmental delay or by motor delay. HYPOTHESIS : Motor delay in the context of global developmental delay is an initial "red flag" for ASD, with added risk in girls. OBJECTIVE : To assess early developmental milestones in girls with ASD as compared to diagnosed boys, considering prematurity risk. METHOD : Developmental milestones in a cohort of 467 children with ASD - diagnosed at mean age of 3.4 years (SD = 2.2) - were analyzed according to gender and prematurity risk. RESULTS : 111 girls (24 %), 356 boys (76 %), presented with motor milestones acquisition grossly within the normal range. However, there was a shift towards acquisition of walking being at the later end of the norm range, with this shift being more prominent in girls. 60 % of girls and 47 % of boys with ASD had motor delay and 49 % of girls and 36 % of boys had global developmental delay. The extent of the delays was greater in the prematurity subgroup. CONCLUSION : Global delay of early milestones occurred in half of children with ASD and in 60 % of girls with ASD. Delayed acquisition of independent walking is relatively more common in girls subsequently diagnosed with ASD.

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4. Ratto AB. Commentary : What’s so special about girls on the autism spectrum ? - a commentary on Kaat et al. (2020). J Child Psychol Psychiatry ;2020 (Jun 19)

This commentary on the multisite integrative analysis of sex differences on gold standard measures of autism by Kaat and colleagues (2020) provides perspective on its contributions to the debate surrounding sex differences in autism. While this study reports important findings regarding sex differences using currently available tools and samples, innovative research approaches are needed to develop new tools and methodologies to improve our understanding of how autism manifests across the gender spectrum. This includes developing meaningful research partnerships with autistic colleagues, actively recruiting more diverse samples, and augmenting conventional tools and methodologies with new, and equally rigorous, approaches.

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5. Schmidt KC, Loutaev I, Quezado Z, Sheeler C, Smith CB. Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome : A L-[1-(11)C]leucine PET study. Neurobiol Dis ;2020 (Jun 19):104978.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein (FMRP), a putative translation suppressor, is absent or significantly reduced in FXS. One prevailing hypothesis is that rates of protein synthesis are increased by the absence of this regulatory protein. In accord with this hypothesis, we have previously reported increased rates of cerebral protein synthesis (rCPS) in the Fmr1 knockout mouse model of FXS and others have reported similar effects in hippocampal slices. To address the hypothesis in human subjects, we applied the L[1-(11)C]leucine PET method to measure rCPS in adults with FXS and healthy controls. All subjects were males between the ages of 18 and 24 years and free of psychotropic medication. As most fragile X participants were not able to undergo the PET study awake, we used dexmedetomidine for sedation during the imaging studies. We found no differences between rCPS measured during dexmedetomidine-sedation and the awake state in ten healthy controls. In the comparison of rCPS in dexmedetomidine-sedated fragile X participants (n = 9) and healthy controls (n = 14) we found no statistically significant differences. Our results from in vivo measurements in human brain do not support the hypothesis that rCPS are elevated due to the absence of FMRP. This hypothesis is based on findings in animal models and in vitro measurements in human peripheral cells. The absence of a translation suppressor may produce a more complex response in pathways regulating translation than previously thought. We may need to revise our working hypotheses regarding FXS and our thinking about potential therapeutics.

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