scholarly journals Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 782
Author(s):  
Veronica Tisato ◽  
Juliana A. Silva ◽  
Giovanna Longo ◽  
Ines Gallo ◽  
Ajay V. Singh ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Mthfr Gene ◽  
Spectrum Disorder ◽  
Fetal Life ◽  
Clinical Phenotypes ◽  
One Carbon Metabolism ◽  
Causes And Risk Factors ◽  
Individual Disease

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10–25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics.

scholarly journals Genomics of autism spectrum disorder: approach to therapy

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 627 ◽  
Author(s):  
Fatma Ayhan ◽  
Genevieve Konopka
Keyword(s):  
Autism Spectrum Disorder ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Spectrum Disorder ◽  
Current State ◽  
Genetics And Genomics

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition with no current treatment available. Although advances in genetics and genomics have identified hundreds of genes associated with ASD, very little is known about the pathophysiology of ASD and the functional contribution of specific genes to ASD phenotypes. Improved understanding of the biological function of ASD-associated genes and how this heterogeneous group of genetic variants leads to the disease is needed in order to develop therapeutic strategies. Here, we review the current state of ASD research related to gene discovery and examples of emerging molecular mechanisms (protein translation and alternative splicing). In addition, we discuss how patient-derived three-dimensional brain organoids might provide an opportunity to model specific genetic variants in order to define molecular and cellular defects that could be amenable for developing and screening personalized therapies related to ASD.

scholarly journals Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Richard E. Frye ◽  
Loïc Lionnard ◽  
Indrapal Singh ◽  
Mohammad A. Karim ◽  
Hanane Chajra ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Mitochondrial Metabolism ◽  
Spectrum Disorder ◽  
Mitochondrial Morphology ◽  
Complex Iv ◽  
Children With Asd

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.

scholarly journals Influence of the Aryl Hydrocarbon Receptor Activating Environmental Pollutants on Autism Spectrum Disorder

2021 ◽  
Vol 22 (17) ◽  
pp. 9258
Author(s):  
Hevna Dhulkifle ◽  
Abdelali Agouni ◽  
Asad Zeidan ◽  
Mohammed Saif Al-Kuwari ◽  
Aijaz Parray ◽  
...  
Keyword(s):  
Risk Factors ◽  
Autism Spectrum Disorder ◽  
Aryl Hydrocarbon Receptor ◽  
Molecular Mechanisms ◽  
Environmental Pollutants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Development Communication ◽  
Aryl Hydrocarbon ◽  
The Impact

Autism spectrum disorder (ASD) is an umbrella term that includes many different disorders that affect the development, communication, and behavior of an individual. Prevalence of ASD has risen exponentially in the past couple of decades. ASD has a complex etiology and traditionally recognized risk factors only account for a small percentage of incidence of the disorder. Recent studies have examined factors beyond the conventional risk factors (e.g., environmental pollution). There has been an increase in air pollution since the beginning of industrialization. Most environmental pollutants cause toxicities through activation of several cellular receptors, such as the aryl hydrocarbon receptor (AhR)/cytochrome P450 (CYPs) pathway. There is little research on the involvement of AhR in contributing to ASD. Although a few reviews have discussed and addressed the link between increased prevalence of ASD and exposure to environmental pollutants, the mechanism governing this effect, specifically the role of AhR in ASD development and the molecular mechanisms involved, have not been discussed or reviewed before. This article reviews the state of knowledge regarding the impact of the AhR/CYP pathway modulation upon exposure to environmental pollutants on ASD risk, incidence, and development. It also explores the molecular mechanisms involved, such as epigenesis and polymorphism. In addition, the review explores possible new AhR-mediated mechanisms of several drugs used for treatment of ASD, such as sulforaphane, resveratrol, haloperidol, and metformin.

scholarly journals Mechanistic Insight Into the Regulation of Immune-Related Genes Expression in Autism Spectrum Disorder

2021 ◽  
Vol 8 ◽  
Author(s):  
Hani Sabaie ◽  
Hossein Dehghani ◽  
Shadi Shiva ◽  
Mohammad Reza Asadi ◽  
Omidvar Rezaei ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Pathway Enrichment Analysis ◽  
Cerna Network ◽  
Immune Related Genes ◽  
Rna Interaction

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder featuring impairment in verbal and non-verbal interactions, defects in social interactions, stereotypic behaviors as well as restricted interests. In recent times, the incidence of ASD is growing at a rapid pace. In spite of great endeavors devoted to explaining ASD pathophysiology, its precise etiology remains unresolved. ASD pathogenesis is related to different phenomena associated with the immune system; however, the mechanisms behind these immune phenomena as well as the potential contributing genes remain unclear. In the current work, we used a bioinformatics approach to describe the role of long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) in the peripheral blood (PB) samples to figure out the molecular regulatory procedures involved in ASD better. The Gene Expression Omnibus database was used to obtain the PB microarray dataset (GSE89594) from the subjects suffering from ASD and control subjects, containing the data related to both mRNAs and lncRNAs. The list of immune-related genes was obtained from the ImmPort database. In order to determine the immune-related differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs), the limma package of R software was used. A protein-protein interaction network was developed for the immune-related DEmRNAs. By employing the Human MicroRNA Disease Database, DIANA-LncBase, and DIANA-TarBase databases, the RNA interaction pairs were determined. We used the Pearson correlation coefficient to discover the positive correlations between DElncRNAs and DEmRNAs within the ceRNA network. Finally, the lncRNA-associated ceRNA network was created based on DElncRNA-miRNA-DEmRNA interactions and co-expression interactions. In addition, the KEGG enrichment analysis was conducted for immune-related DEmRNAs found within the constructed network. This work found four potential DElncRNA-miRNA-DEmRNA axes in ASD pathogenesis, including, LINC00472/hsa-miR-221-3p/PTPN11, ANP32A-IT1/hsa-miR-182-5p/S100A2, LINC00472/hsa-miR-132-3p/S100A2, and RBM26-AS1/hsa-miR-182-5p/S100A2. According to pathway enrichment analysis, the immune-related DEmRNAs were enriched in the “JAK-STAT signaling pathway” and “Adipocytokine signaling pathway.” An understanding of regulatory mechanisms of ASD-related immune genes would provide novel insights into the molecular mechanisms behind ASD pathogenesis.

scholarly journals Convergent Canonical Pathways in Autism Spectrum Disorder from Proteomic, Transcriptomic and DNA Methylation Data

2021 ◽  
Author(s):  
Caitlyn Mahony ◽  
Colleen O'Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Differentially Expressed ◽  
Methylation Data ◽  
Differentially Expressed Proteins ◽  
Canonical Pathways

Abstract: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic func-tional enrichment signatures to those of transcriptomic and epigenomic data. We iden-tify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD tran-scriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell pro-liferation and differentiation, metabolism and inflammation which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.

scholarly journals Sex Differences in Diagnosis and Clinical Phenotypes of Chinese Children with Autism Spectrum Disorder

2017 ◽  
Vol 33 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Shihuan Wang ◽  
Hongzhu Deng ◽  
Cong You ◽  
Kaiyun Chen ◽  
Jianying Li ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Sex Differences ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chinese Children ◽  
Clinical Phenotypes

scholarly journals Autism Spectrum Disorder and Disruptive Behavior Disorders Comorbidities Delineate Clinical Phenotypes in Attention-Deficit Hyperactivity Disorder: Novel Insights from the Assessment of Psychopathological and Neuropsychological Profiles

2020 ◽  
Vol 9 (12) ◽  
pp. 3839
Author(s):  
Gianluca Sesso ◽  
Chiara Cristofani ◽  
Stefano Berloffa ◽  
Paola Cristofani ◽  
Pamela Fantozzi ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Attention Deficit Hyperactivity Disorder ◽  
Executive Functions ◽  
Disruptive Behavior ◽  
Attention Deficit ◽  
Behavior Disorders ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Clinical Phenotypes ◽  
Hyperactivity Disorder

Although childhood-onset psychiatric disorders are often considered as distinct and separate from each other, they frequently co-occur, with partial overlapping symptomatology. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) commonly co-occur with each other and with other mental disorders, particularly disruptive behavior disorders, oppositional defiant disorder/conduct disorder (ODD/CD). Whether these associated comorbidities represent a spectrum of distinct clinical phenotypes is matter of research. The aim of our study was to describe the clinical phenotypes of youths with ADHD with and without ASD and/or ODD/CD, based on neuropsychological and psychopathological variables. One-hundred fifty-one participants with ADHD were prospectively recruited and assigned to four clinical groups, and assessed by means of parent-reported questionnaires, the child behavior checklist and the behavior rating inventory of executive functions. The ADHD alone group presented a greater impairment in metacognitive executive functions, ADHD+ASD patients presented higher internalizing problems and deficits in Shifting tasks, and ADHD+ODD/CD subjects presented emotional-behavioral dysregulation. Moreover, ADHD+ASD+ODD/CD individuals exhibited greater internalizing and externalizing problems, and specific neuropsychological impairments in the domains of emotional regulation. Our study supports the need to implement the evaluation of the psychopathological and neuropsychological functioning profiles, and to characterize specific endophenotypes for a finely customized establishment of treatment strategies.

scholarly journals Frequency of MTHFR GENE C677T Polymorphism for Non-Syndromic Autism Spectrum Disorder Patients

2015 ◽  
Vol 1 (2) ◽  
pp. 33
Author(s):  
Bremmy Laksono ◽  
Ani Melani Maskoen ◽  
Tri Indah Winarni ◽  
Syarief Taufik ◽  
Sultana MH Faradz
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Spectrum Disorder ◽  
C677t Polymorphism ◽  
Wild Type ◽  
Mutant Type ◽  
Syndromic Autism ◽  
Syndromic Asd

Background: The folate metabolism is a pathway that may involve in the non-syndromic Autism Spectrum Disorder (ASD). Methylenetetrahydrofolate reductase enzyme has a key role in folate metabolism. The C677T polymorphism of MTHFR gene could reduce the effectiveness of the enzyme.Objectives: To evaluate the frequency of MTHFR geneC677T polymorphism for non-syndromic ASD patients.Method: Thirty-four DNA samples were taken from each group. PCR mixture was consisted of 1µL DNA, 2.5µL PCR buffer, 0.5µL dNTP, 1.5µL MgCL2, 0.125µLTaqenzyme, 0.5µLofforwardandreverseprimerandaquabidesttoreach a volume of 25 µL. The PCR profiles were initiation 95ºC for 5 min, denaturation 94ºC for 1min, annealing 55ºCfor 45 seconds, and elongation 72ºC for30 seconds. The cycles were done in 35 times an dfinal elongation was at 72ºC for 5min. The PCR product was 198bp, and then digested by the Hinfl enzyme for 16hours at 37°C, and visualized using2%agarosegeland then electrophoresed for 30 minutes at 100 volts.Result: Non-syndromic ASD samples showed none had homozygote mutant type (677TT), 3 (8.8%) samples had heterozygote (677CT)and 31 (91.2%) samples had wild type (677CC). Meanwhile, normal control showed only 1 (2.9%)sample had homozygote mutant type(677TT), 9 (26.5%) samples had heterozygote (677CT)and 24 (70.6%) samples had  wild type (677CC).Conclusion: The frequency of MTHFR geneC677T polymorphism in patients with non-syndromic ASD and controls are not significantly different.

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