Role of the PTEN signaling pathway in autism spectrum disorder.
Ontology highlight
ABSTRACT:
SUBMITTER: Lv JW
PROVIDER: S-EPMC5562549 | biostudies-other | 2013 Dec
REPOSITORIES: biostudies-other
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Project description:Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.
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Project description:Autism spectrum disorder (ASD) is a series of neurodevelopmental disorder with a large genetic component. However, the pathogenic genes and molecular mechanisms of ASD have not been clearly defined. Recent technological advancements, such as next-generation sequencing, have led to the identification of certain loci that is responsible for the pathophysiology of ASD. Three functional pathways, such as chromatin remodeling, Wnt signaling and mitochondrial dysfunction are potentially involved in ASD. In this review, we will focus on recent studies of the involvement of Wnt signaling pathway components in ASD pathophysiology and related drugs used in ASD treatment.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-27 | GSE111176 | GEO
Project description:Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.
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Project description:The exact pathogenesis of autism spectrum disorder (ASD) is still unclear, yet some potential mechanisms may not have been evaluated before. Cuproptosis is a novel form of regulated cell death reported this year, and no study has reported the relationship between ASD and cuproptosis. This study aimed to identify ASD in suspected patients early using machine learning models based on biomarkers of the cuproptosis pathway. We collected gene expression profiles from brain samples from ASD model mice and blood samples from humans with ASD, selected crucial genes in the cuproptosis signaling pathway, and then analysed these genes with different machine learning models. The accuracy, sensitivity, specificity, and areas under the receiver operating characteristic curves of the machine learning models were estimated in the training, internal validation, and external validation cohorts. Differences between models were determined with Bonferroni's test. The results of screening with the Boruta algorithm showed that FDX1, DLAT, LIAS, and ATP7B were crucial genes in the cuproptosis signaling pathway for ASD. All selected genes and corresponding proteins were also expressed in the human brain. The k-nearest neighbor, support vector machine and random forest models could identify approximately 72% of patients with ASD. The artificial neural network (ANN) model was the most suitable for the present data because the accuracy, sensitivity, and specificity were 0.90, 1.00, and 0.80, respectively, in the external validation cohort. Thus, we first report the prediction of ASD in suspected patients with machine learning methods based on crucial biomarkers in the cuproptosis signaling pathway, and these findings may contribute to investigations of the potential pathogenesis and early identification of ASD.
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Project description:Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.
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Project description:The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.
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Project description:The aim of this study was to identify ASD vulnerability components, explore possible vulnerability subgroups, and evaluate environmental contribution to phenotypic variability. We performed PCA and cluster analysis using ASD risk factor data. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 a higher correlation with biological factors (Psychiatric Family History and Gestational Complications). Clustering analysis of PCA scores using bootstrap approach showed two clusters. Comparing the methylome between clusters we found 11.879 DMPs (p<0.05), and their CpG sites were enriched in VMRs, most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability score moderated by epigenetic clock was associated with Vineland Total score (p=0.0036, adjR2=0.31), suggesting risk factors with stress burden can influence phenotype.
2021-10-01 | GSE164563 | GEO
Project description:Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. The Akt/mammalian target of rapamycin (mTOR) pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. In this study, we examined the activity of the Akt/mTOR pathway in cells isolated from children with ASD and typically developing controls. We observed higher activity of mTOR, extracellular receptor kinase, and p70S6 kinase and lower activity of glycogen synthase kinase 3 (GSK3)α and tuberin (TSC2) in cells from children with ASD. These data suggest a phosphorylation pattern indicative of higher activity in the Akt/mTOR pathway in children with general/idiopathic ASD and may suggest a common pathological pathway of interest for ASD.
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Project description:BackgroundGenetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).AbstractGiven the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling "hubs" where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.ConclusionsWe will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.
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