scholarly journals An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes

2021 ◽  
Vol 118 (6) ◽  
pp. e2021429118
Author(s):  
Tal Yardeni ◽  
Ana G. Cristancho ◽  
Almedia J. McCoy ◽  
Patrick M. Schaefer ◽  
Meagan J. McManus ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Seizure Threshold ◽  
Loss Of Function ◽  
Restricted Interests ◽  
Mtdna Mutations ◽  
Mitochondrial Defects ◽  
Mtdna Variants

Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.

Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Pappu Ananya ◽  
Michael Binder ◽  
Yang Wanjun ◽  
Rebecca McClellan ◽  
Brittney Murray ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Left Ventricular ◽  
Individual Risk ◽  
Myocardial Tissue ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Ventricular Tissue ◽  
Mtdna Variants

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.

scholarly journals Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase

Life ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 215
Author(s):  
Qiuju Ding ◽  
Róża Kucharczyk ◽  
Weiwei Zhao ◽  
Alain Dautant ◽  
Shutian Xu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Single Individual ◽  
Loss Of Function ◽  
Mtdna Mutations ◽  
Atp6 Gene ◽  
Novel Variant ◽  
Functional Consequences ◽  
Mtdna Variants

With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20–30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health.

scholarly journals SOCIAL STATUS AND GUT MICROBIAL DYSBIOSIS IN ADULTS AND CHILDREN WITH AUTISM SPECTRUM DISORDERS: A PROFOUND REVIEW OF THE AVAILABLE LITERATURE SOURCES

2021 ◽  
Vol 27 (3) ◽  
pp. 3939-3946
Author(s):  
Sevginar Ibryamova ◽  
◽  
Veselin Petkov ◽  
Tsveteslava Ignatova-Ivanova ◽  
Georgi Kolev ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Behavioral Problems ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Diagnostic Methods ◽  
Restricted Interests ◽  
Microbial Dysbiosis ◽  
Gastrointestinal Problems ◽  
Adults And Children ◽  
Spectrum Disorders

Autism is a complex disorder without a specific diagnosis, so the disease is defined by its specific characteristics described in the literature as cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation. There are many models in the literature explaining the biology of autism, which are based on genetics, immunity, various environmental factors and diet. There is a lot of literature data that people with Autism Spectrum Disorders (ASD) often have gastrointestinal problems that also affect their behavior. ASD suffer developmental disabilities from an early age, which can be both physical and psychological. Often people suffer these problems even throughout their lives. This review aims to provide basic information on definitions, historical data, diagnostic methods, behavioral etiology, gastrointestinal and social problems in adults and children with ASD.

scholarly journals Linking Autism Risk Genes to Disruption of Cortical Development

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2500
Author(s):  
Marta Garcia-Forn ◽  
Andrea Boitnott ◽  
Zeynep Akpinar ◽  
Silvia De Rubeis
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Neurodevelopmental Disorder ◽  
Cortical Development ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genome Wide Association Studies ◽  
Restricted Interests ◽  
Risk Genes ◽  
Whole Exome

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

scholarly journals Recent Advances in Understanding the Genetic Architecture of Autism

2020 ◽  
Vol 21 (1) ◽  
pp. 289-304 ◽  
Author(s):  
Caroline M. Dias ◽  
Christopher A. Walsh
Keyword(s):  
Genetic Architecture ◽  
De Novo ◽  
Clinical Care ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Recent Advances ◽  
Insight Into

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes—have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Moreover, inherited variants (including common variants) and, more recently, rare recessive inherited variants have come into greater focus. Finally, noncoding variants—both inherited and de novo—have been implicated in the last few years. This work has revealed a convergence of diverse genetic drivers on common biological pathways and has highlighted the ongoing importance of increasing sample size and experimental innovation. Continuing to synthesize these genetic findings with functional and phenotypic evidence and translating these discoveries to clinical care remain considerable challenges for the field.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

scholarly journals Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 28
Author(s):  
Iris W. Riemersma ◽  
Robbert Havekes ◽  
Martien J. H. Kas
Keyword(s):  
Autism Spectrum Disorder ◽  
Gene Function ◽  
Current Knowledge ◽  
Developmental Trajectories ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Restricted Interests ◽  
Highly Correlated

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

scholarly journals Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study

2020 ◽  
Vol 10 (4) ◽  
pp. 160
Author(s):  
Sara Calderoni ◽  
Ivana Ricca ◽  
Giulia Balboni ◽  
Romina Cagiano ◽  
Denise Cassandrini ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Microarray Analysis ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Single Center ◽  
Accurate Identification ◽  
Chromosome Microarray Analysis ◽  
Spectrum Disorders ◽  
Chromosome Microarray

Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD). In this framework, we aim to evaluate the frequency of causative CNVs in a single-center cohort of idiopathic f-ASD. Among the 90 f-ASD analyzed, we found 20 patients with one or two potentially pathogenic CNVs, including those previously associated with ASD (located at 16p13.2 16p11.2, 15q11.2, and 22q11.21 regions). An exploratory genotype/phenotype analysis revealed that the f-ASD with causative CNVs had statistically significantly lower restrictive and repetitive behaviors than those without CNVs or with non-causative CNVs. Future work should focus on further understanding of f-ASD genetic underpinnings, taking advantage of next-generation sequencing technologies, with the ultimate goal of contributing to precision medicine in ASD.

Development of a Robotic Motor Skills Assessment System for Children With Autism

2017 ◽  
Author(s):  
Guru Subramani ◽  
Aubrey M. Fisher ◽  
Moria F. Bittmann ◽  
Andrea H. Mason ◽  
Brittany G. Travers ◽  
...  
Keyword(s):  
Social Interactions ◽  
Motor Skills ◽  
Upper Limb ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Assessment System ◽  
Skills Assessment ◽  
Robot Arm ◽  
Restricted Interests

Autism is a developmental disorder characterized by atypical social interactions and repetitive behaviors/restricted interests[1]. It is found that children with autism also experience delayed or impaired motor skills development [2]. It would be advantageous to develop methods that precisely evaluate these motor skills impairments. The use of robots for evaluating upper limb motor competency have been looked at in the stroke literature [3]. We would like to leverage robotic tools for motor skills assessment but with focus for children with autism spectrum disorder. Robotic methodologies provide a unique way of testing upper limb motor skills. For instance, if a person holds on to the end of a robot arm and moves the robot arm in space, the robot can apply forces and prevent or assist the person with these motions. In this fashion, the robot can apply perturbations in a repeatable and precise manner with high fidelity. Since individuals with autism have anxieties interacting with other individuals[4], using an impersonal robot would alleviate the anxiety of social interactions. These individuals learn motor skills best with consistent repetition and strong reinforcement, qualities that robots provide. Therefore, a robot based evaluation strategy and therapy paradigm for children with Autism would be beneficial for the community.

scholarly journals Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1376
Author(s):  
Alba Pensado-López ◽  
Sara Veiga-Rúa ◽  
Ángel Carracedo ◽  
Catarina Allegue ◽  
Laura Sánchez
Keyword(s):  
Autism Spectrum Disorders ◽  
Autism Spectrum ◽  
Experimental Models ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Complex Disorder ◽  
Spectrum Disorders ◽  
Associated Risk Factors

Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.

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