Abstract
Autism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behavior, interests, or activities [1]
Since we hypothesized that the EPHB2 Q857X mutation contributes to the female patient’s ASD phenotype, we examined the effects of global disruption of one EphB2 allele (EphB2+/−) in both male and female mice to assess the potential of EPHB2 hypofunction for producing ASDassociated behaviors and/or altered cortical neuron function
Detection of rare, nonsynonymous single nucleotide variants in EPHB2 gene The identification of the de novo nonsense mutation (Q857X) revealed EPHB2 as a candidate risk gene for ASD [13]. To explore this possibility further, we examined the results of a separate project involving PCR amplification and Sanger sequencing across all EPHB2 coding exons in 864 ASD probands and both biological parents from the Simons Simplex Collection (SSC) [20] and 831 unrelated individuals from the National Institute of Neurological Disorders and Stroke (NINDS) Neurologically Normal Caucasian Control Panel
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behavior, interests, or activities [1]. De novo and rare, inherited copy number variants and single nucleotide variants (SNVs) affecting hundreds of genes have been associated with ASD [4]. This genetic heterogeneity likely contributes to the well-described variation in ASD symptom severity and the presence or absence of common comorbidities, like intellectual disability (ID), attentiondeficit hyperactivity disorder (ADHD), anxiety disorders, sleep disruptions, changes in sensitivity to sensory stimuli, and gastrointestinal problems [5]. Testing whether and how a candidate ASD risk gene produces ASD-associated symptoms remains a major challenge in human patients. Linking genotype to phenotype could provide key insights into the role of a specific gene in ASD pathophysiology and a path toward developing personalized treatments for affected individuals
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