Pubmed du 02/05/21
1. Horiuchi F, Yoshino Y, Kumon H, Hosokawa R, Nakachi K, Kawabe K, Iga JI, Ueno SI. Identification of aberrant innate and adaptive immunity based on changes in global gene expression in the blood of adults with autism spectrum disorder. Journal of neuroinflammation. 2021; 18(1): 102.
BACKGROUND: Autism spectrum disorder (ASD) is characterized as a neurodevelopmental disorder, and one of the main hypotheses regarding its cause is genetic factors. A previous meta-analysis of seven microarray studies and one RNA sequencing (RNA-seq) study using the blood of children with ASD identified dysregulation of gene expressions relevant to the immune system. In this study, we explored changes in global gene expression as the phenotype of ASD in the blood of adults with ASD. METHODS: We recruited an RNA-seq cohort (ASD vs. control; n = 6 each) and a replication cohort (ASD vs. control; n = 19 each) and conducted RNA-seq to explore changes in global gene expression. We then subjected the significantly up- and downregulated genes to gene ontology (GO) and core analyses. Weighted gene correlation network analysis (WGCNA) was performed with all 11,617 genes detected in RNA-seq to identify the ASD-specific gene network. RESULTS: In total, 117 significantly up- and 83 significantly downregulated genes were detected in the ASD compared with the control group, respectively (p < 0.05 and q < 0.05). GO analysis revealed that the aberrant innate and adaptive immunity were more obvious in the 117 upregulated than in the 83 downregulated genes. WGCNA with core analysis revealed that one module including many immune-related genes was associated with the natural killer cell signaling pathway. In the results for the replication cohort, significant changes with same trend found in RNA-seq data were confirmed for MAFB (p = 0.046), RPSAP58 (p = 0.030), and G2MK (p = 0.004). LIMITATIONS: The sample size was relatively small in both the RNA-seq and replication cohorts. This study examined the mRNA expression level, so the interaction between mRNA and protein remains unclear. The expression changes between children and adults with ASD were not compared because only adults with ASD were targeted. CONCLUSIONS: The dysregulated gene expressions confirmed in the blood of adults with ASD were relevant to the dysfunction of innate and adaptive immunity. These findings may aid in understanding the pathogenesis of ASD.
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2. Leblond CS, Le TL, Malesys S, Cliquet F, Tabet AC, Delorme R, Rolland T, Bourgeron T. Operative list of genes associated with autism and neurodevelopmental disorders based on database review. Molecular and cellular neurosciences. 2021; 113: 103623.
The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD.
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3. Manjeese W, Mvubu NE, Steyn AJC, Mpofana T. Mycobacterium tuberculosis causes a leaky blood-brain barrier and neuroinflammation in the prefrontal cortex and cerebellum regions of infected mice offspring. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2021; 81(5): 428-37.
The maternal system’s exposure to pathogens influences foetal brain development through the influx of maternal cytokines and activation of the foetal immune status to a persistent inflammatory state characterised by glia cell activation. Neuroinflammation influences the blood-brain barrier’s (BBB) permeability allowing peripheral immune cell trafficking into the brain. Mycobacterium tuberculosis (Mtb) is a pathogen that causes Tuberculosis (TB), a global pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of Autism spectrum disorder (ASD), it is not known whether gestational Mtb infections also contribute to impaired foetal neurodevelopment. Here we infect pregnant Balb/c mice with Mtb H37Rv and Valproic acid (VPA) individually and in combination. Neuroinflammation was measured by assessing microglia and astrocyte population in the prefrontal cortex (PFC) and cerebellum (CER) of pups. Mtb infection increased the microglia population and caused morphological changes to a reactive phenotype in the PFC. Also, the astrocyte population was significantly increased in the PFC of Mtb pups. The BBB permeability was determined by measuring the Evans Blue (EB) dye concentration in the PFC and CER 1 hr post receiving intravenous EB-dye injection. We found that prenatal Mtb exposure significantly increased the BBB’s permeability in the PFC and CER of pups versus saline. Overall, our data demonstrate that prenatal exposure to Mtb predisposes offspring to a higher risk of BBB damage while inducing persistent neuroinflammation, which could lead to impaired neuronal development and function. These findings implicate a potential role of gestational Mtb infections in the aetiology of ASD.
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4. Rodriguez-Fontenla C, Carracedo A. UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes. Translational psychiatry. 2021; 11(1): 256.
Autism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.
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5. Rogers AP, Friend K, Rawlings L, Barnett CP. A de novo missense variant in MED13 in a patient with global developmental delay, marked facial dysmorphism, macroglossia, short stature, and macrocephaly. American journal of medical genetics Part A. 2021; 185(8): 2586-92.
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6. Suzumura N, Nishida T, Maki N, Komeda H, Kawasaki M, Funabiki Y. Atypical cortical activation during fine motor tasks in autism spectrum disorder. Neuroscience research. 2021; 172: 92-8.
Individuals with autism spectrum disorder (ASD) often have difficulty with coordinated fine motor skills, but the degree of difficulty significantly varies from person to person. To elucidate the cause of this diversity, we monitored brain activity during fine movement tasks (tying bowknots) by near-infrared spectroscopy in 17 adults with ASD and 18 adults with typical development matched for age, gender, and intelligence quotient (IQ). We also examined the relationship between brain activation and developmental characteristics, including ASD severity, using the Autism-Spectrum Quotient and the Multi-dimensional Scale for Pervasive Developmental Disorder and Attention-Deficit/Hyperactivity Disorder. Although participants in the ASD group did not show significant clumsiness, their right prefrontal cortexes were relatively less activated, particularly in individuals with poor social skills and inattention. Our study indicates that individuals with ASD traits may use different strategies when performing fine movements; that is, they less use the brain areas responsible for processing visual image or planning behaviors.
