scholarly journals Towards a gene-level map of resilience to genetic variants associated with autism

2021 ◽  
Author(s):  
Thomas Rolland ◽  
Freddy Cliquet ◽  
Richard J.L. Anney ◽  
Nicolas Traut ◽  
Alexandre Mathieu ◽  
...  
Keyword(s):  
Genetic Data ◽  
Autism Spectrum ◽  
Common Variants ◽  
Loss Of Function ◽  
Polygenic Scores ◽  
Gene Level ◽  
Clinical Profiles ◽  
Males And Females ◽  
Spectrum Disorders ◽  
Genetic Profiles

ABSTRACTWhile over 100 genes are now significantly associated with autism spectrum disorders (ASD), the penetrance of the variants affecting these genes remains poorly understood. Here, we quantified the prevalence of rare loss-of-function (LoF) mutations affecting 156 genes robustly associated with ASD (SPARK genes) using genetic data from more than 10,000 individuals with ASD and 100,000 undiagnosed individuals. We then investigated the clinical, brain imaging and genetic profiles of individuals heterozygous for these rare deleterious variants who were not diagnosed with ASD. These “resilient” individuals, observed in less than 1% of the general population, were equally distributed among males and females, but displayed low polygenic scores for ASD compared to LoF heterozygotes diagnosed with ASD. The interplay between rare and common variants may therefore contribute to the clinical profiles of the individuals carrying LoF in genes associated with ASD.

scholarly journals Sex-Specific Social Behavior and Amygdala Proteomic Deficits in Foxp2+/− Mutant Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Maria Jesus Herrero ◽  
Li Wang ◽  
David Hernandez-Pineda ◽  
Payal Banerjee ◽  
Heidi Y. Matos ◽  
...  
Keyword(s):  
Social Behavior ◽  
Social Interactions ◽  
Social Behaviors ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Neuronal Communication ◽  
Males And Females ◽  
Spectrum Disorders ◽  
Encoding Gene ◽  
Dopamine Signaling

In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum Disorders (ASD), the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/– heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive, and parental behaviors. Interestingly, some of these deficits are displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue. This analyses revealed putative sex differences expression of a host of proteins implicated in neuronal communication, connectivity, and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.

scholarly journals Individual common variants exert weak effects on the risk for autism spectrum disorders

2012 ◽  
Vol 21 (21) ◽  
pp. 4781-4792 ◽  
Author(s):  
Richard Anney ◽  
Lambertus Klei ◽  
Dalila Pinto ◽  
Joana Almeida ◽  
Elena Bacchelli ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Autism Spectrum ◽  
Common Variants ◽  
Spectrum Disorders

scholarly journals Determination of psychosis-related clinical profiles in children with autism spectrum disorders using latent class analysis

2014 ◽  
Vol 24 (3) ◽  
pp. 301-307 ◽  
Author(s):  
Marinos Kyriakopoulos ◽  
Argyris Stringaris ◽  
Sofia Manolesou ◽  
Maja Drobnič Radobuljac ◽  
Brian Jacobs ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Latent Class Analysis ◽  
Latent Class ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Class Analysis ◽  
Clinical Profiles ◽  
Spectrum Disorders

No association between common variants in glyoxalase 1 and autism spectrum disorders

2007 ◽  
Vol 147B (1) ◽  
pp. 124-127 ◽  
Author(s):  
Karola Rehnström ◽  
Tero Ylisaukko-oja ◽  
Raija Vanhala ◽  
Lennart von Wendt ◽  
Leena Peltonen ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Autism Spectrum ◽  
Common Variants ◽  
Glyoxalase 1 ◽  
Spectrum Disorders

scholarly journals Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders

2013 ◽  
Vol 19 (8) ◽  
pp. 872-879 ◽  
Author(s):  
E M Kenny ◽  
P Cormican ◽  
S Furlong ◽  
E Heron ◽  
G Kenny ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Spectrum Disorders

scholarly journals Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xiangling Meng ◽  
Wei Wang ◽  
Hui Lu ◽  
Ling-jie He ◽  
Wu Chen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Neurological Disorders ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Loss Of Function ◽  
Glutamatergic Neurons ◽  
Excitatory Neurotransmission ◽  
Spectrum Disorders

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition

2020 ◽  
Vol 30 (12) ◽  
pp. 6313-6324
Author(s):  
Davide Bassetti ◽  
Aniello Lombardi ◽  
Sergei Kirischuk ◽  
Heiko J Luhmann
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Tumor Suppressor Genes ◽  
Time Window ◽  
Gabab Receptor ◽  
Brain Slices ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Electrophysiological Recordings ◽  
Spectrum Disorders

Abstract Loss-of-function mutation in one of the tumor suppressor genes TSC1 or TSC2 is associated with several neurological and psychiatric diseases, including autism spectrum disorders (ASDs). As an imbalance between excitatory and inhibitory neurotransmission, E/I ratio is believed to contribute to the development of these disorders, we investigated synaptic transmission during the first postnatal month using the Tsc2+/− mouse model. Electrophysiological recordings were performed in acute brain slices of medial prefrontal cortex. E/I ratio at postnatal day (P) 15–19 is increased in Tsc2+/− mice as compared with wildtype (WT). At P25–30, facilitated GABAergic transmission reduces E/I ratio to the WT level, but weakening of tonic GABAB receptor (GABABR)-mediated inhibition in Tsc2+/− mice leads to hyperexcitability both at single cell and neuronal network level. Short (1 h) preincubation of P25–30 Tsc2+/− slices with baclofen restores the GABABR-mediated inhibition and reduces network excitability. Interestingly, the same treatment at P15–19 leads to weakening of GABABR-mediated inhibition. We hypothesize that a dysfunction of tonic GABABR-mediated inhibition might contribute to the development of ASD symptoms and suggest that GABABR activation within an appropriate time window may be considered as a therapeutic target in ASD.

scholarly journals CHD8 safeguards early neuroectoderm differentiation in human ESCs and protects from apoptosis during neurogenesis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Song Ding ◽  
Xianchun Lan ◽  
Yajing Meng ◽  
Chenchao Yan ◽  
Mao Li ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Autism Spectrum ◽  
Directed Differentiation ◽  
Loss Of Function ◽  
Human Escs ◽  
Chromatin Remodelers ◽  
Spectrum Disorders ◽  
Pluripotency Maintenance

AbstractThe chromatin remodeler CHD8, which belongs to the ATP-dependent chromatin remodelers CHD family, is one of the most high-risk mutated genes in autism spectrum disorders. However, the role of CHD8 in neural differentiation and the mechanism of CHD8 in autism remains unclear, despite there are a few studies based on the CHD8 haploinsufficient models. Here, we generate the CHD8 knockout human ESCs by CRISPR/Cas9 technology and characterize the effect of loss-of-function of CHD8 on pluripotency maintenance and lineage determination by utilizing efficient directed differentiation protocols. The results show loss-of-function of CHD8 does not affect human ESC maintenance although having slight effect on proliferation and cell cycle. Interestingly, CHD8 depletion results in defective neuroectoderm differentiation, along with severe cell death in neural progenitor stage. Transcriptome analysis also indicates CHD8 does not alter the expression of pluripotent genes in ESC stage, but in neural progenitor cells depletion of CHD8 induces the abnormal expression of the apoptosis genes and suppresses neuroectoderm-related genes. These results provide the evidence that CHD8 plays an essential role in the pluripotency exit and neuroectoderm differentiation as well as the regulation of apoptosis during neurogenesis.

scholarly journals Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

2021 ◽  
Vol 14 ◽  
Author(s):  
Mario O. Caracci ◽  
Miguel E. Avila ◽  
Francisca A. Espinoza-Cavieres ◽  
Héctor R. López ◽  
Giorgia D. Ugarte ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Cell Fate ◽  
Pyramidal Neurons ◽  
Cell Types ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
High Confidence ◽  
Developmental Abnormalities ◽  
Cell Fate Decisions ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

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