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 Local Protein Translation and RNA Processing of Synaptic Proteins in Autism Spectrum Disorder

2021 ◽  
Vol 22 (6) ◽  
pp. 2811
Author(s):  
Yuyoung Joo ◽  
David R. Benavides
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Synaptic Proteins ◽  
Local Translation ◽  
Translation Control

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition associated with impairments in social interaction, communication and repetitive behaviors. While the underlying disease mechanisms remain to be fully elucidated, dysfunction of neuronal plasticity and local translation control have emerged as key points of interest. Translation of mRNAs for critical synaptic proteins are negatively regulated by Fragile X mental retardation protein (FMRP), which is lost in the most common single-gene disorder associated with ASD. Numerous studies have shown that mRNA transport, RNA metabolism, and translation of synaptic proteins are important for neuronal health, synaptic plasticity, and learning and memory. Accordingly, dysfunction of these mechanisms may contribute to the abnormal brain function observed in individuals with autism spectrum disorder (ASD). In this review, we summarize recent studies about local translation and mRNA processing of synaptic proteins and discuss how perturbations of these processes may be related to the pathophysiology of ASD.

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 Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hidekazu Kato ◽  
Itaru Kushima ◽  
Daisuke Mori ◽  
Akira Yoshimi ◽  
Branko Aleksic ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Histone Methylation ◽  
Genetic Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Gene Encoding ◽  
Rare Genetic Variants ◽  
Lysine Demethylase ◽  
Methylation Patterns ◽  
Sample Set

AbstractDysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

Evaluation of Overhand Throwing Among College Students With and Without Autism Spectrum Disorder

2021 ◽  
Vol 38 (1) ◽  
pp. 43-61
Author(s):  
Teri A. Todd ◽  
Keely Ahrold ◽  
Danielle N. Jarvis ◽  
Melissa A. Mache
Keyword(s):  
College Students ◽  
Autism Spectrum Disorder ◽  
Young Adults ◽  
Three Dimensional ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Overhand Throw ◽  
Ball Velocity ◽  
Overhand Throwing ◽  
Adults With Asd

Children with autism spectrum disorder (ASD) typically demonstrate deficits in gross motor skills such as the overhand throw. It has not been determined whether such deficits persist into adulthood. Therefore, the purpose of this study was to examine the kinematics and developmental level of overhand throws among young adults with and without ASD. Three-dimensional motion-capture data were collected during overhand throwing trials performed by 20 college students (10 students with ASD). Individuals with ASD demonstrated similar throw duration, stride length, and step width but a longer acceleration phase and slower ball velocity than individuals without ASD. Young adults with ASD also performed the overhand throw with less developmental proficiency than those without ASD. Specifically, individuals with ASD exhibited developmental deficits in the backswing and composite throwing score. Motor skill interventions for individuals with ASD should address throwing skills, with a particular focus on the preparatory phase of the overhand throw.

scholarly journals Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

2013 ◽  
Vol 93 (2) ◽  
pp. 249-263 ◽  
Author(s):  
Yong-hui Jiang ◽  
Ryan K.C. Yuen ◽  
Xin Jin ◽  
Mingbang Wang ◽  
Nong Chen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Whole Genome

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.

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