Two de novo variants (one nonsense, one missense) in the EPHB2 gene were identified in separate next-generation sequencing reports using ASD probands (Sanders et al., 2012; Kong et al., 2012).
Molecular Function
This gene encodes a member of the Eph receptor family of receptor tyrosine kinase transmembrane glycoproteins. These receptors are composed of an N-terminal glycosylated ligand-binding domain, a transmembrane region and an intracellular kinase domain. They bind ligands called ephrins and are involved in diverse cellular processes including motility, division, and differentiation. A distinguishing characteristic of Eph-ephrin signaling is that both receptors and ligands are competent to transduce a signaling cascade, resulting in bidirectional signaling. This protein belongs to a subgroup of the Eph receptors called EphB. Proteins of this subgroup are distinguished from other members of the family by sequence homology and preferential binding affinity for membrane-bound ephrin-B ligands.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
An EphB2 humanized mutation identified from an ASD proband shows ASD-like social behaviors, such as decreased social approach and interaction. An EphB2 knockout mutant also shows social behavior deficits. Social stimulus-dependent neuronal activation is ablated in the mutant mice. Mutant mice also show deficits in synaptic transmission in the dorsomedial prefrontal cortex neurons. Social stimulus-dependent neuronal activation can be restored through synchronous optogenetic activation of the prefrontal cortex, of both the subject (mutant) and partner mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Ephb2 knockout mutation (MGI:2149765) was generated through homologous recombination in embryonic stem cells by deleting a 1.4-kb segment of the Ephb2 locus and inserting a neomycin resistance cassette. This deletion, which encompasses the exon for amino acids 29-50, generates a protein null allele, by introducing a frameshift downstream from the deletion.
Allele Type: Knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129
ES Cell Line: R1
Mutant ES Cell Line: Model Source: Tony Pawson lab (PMID 8689685)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The humanized knockin nonsense mutation c.2572 C > T (Q858X) introduces a premature termination codon in exon 14 of the EphB2 protein. This mutation is identified in a large-scale study of de novo mutations in ASD probands, Sanders et al. 2012 (PMID 22495306). Mutation was introduced using a two-step process using a targeting vector with the mutation and a neomycin resistance cassette flanked by LoxP sites. The neo cassette was later removed by crossing with mice carrying the ubiquitous ALLA-cre driver.
Allele Type: ASD mutation
Strain of Origin: Not specified
Genetic Background: 129
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Nan-Jie Xu lab (PMID 36802416)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The humanized knockin missense mutation G > A (G900S) introduces an amino acid change in exon 14 of the EphB2 protein. This mutation is identified in a large-scale study of de novo mutations in ASD and schizophrenia probands, Kong et al. 2012 (PMID 22914163). Mutation was introduced using a two-step process using a targeting vector with the mutation and a neomycin resistance cassette flanked by LoxP sites. The neo cassette was later removed by crossing with mice carrying the ubiquitous ALLA-cre driver.
Allele Type: NDD mutation
Strain of Origin: Not specified
Genetic Background: 129
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Nan-Jie Xu lab (PMID 36802416)
Description: Knockout mice exhibit reduced social interaction measured by time sniffing of conspecific partner versus time sniffing an empty cage. Knockout mice show reduced time sniffing partner and no change in sniffing empty cage, compared to wildtype mice.
Description: Knockout mice exhibit a reduced sociability index compared to wildtype mice, indicating that they have a reduced preference ratio for a conspecific partner over an empty cage. Social approach was also measured by time spent near the partner or empty cage, and knockout mice exhibit reduced time in the vicinity of of the partner and increased time in the vicinity of the empty cage compared to control mice. Knockout mice also show reduce time for each individual approach or epoch.
Description: Expression of EphB2 protein in ablated in brain tissue from knockout mice. Decrease is observed in both the immunoprecipitate fraction and total brain lysate.
Description: GluA1 and GluA2 protein levels are reduced in the synaptosomal fraction of cortical tissue from knockin mice compared to wildtype.
Exp Paradigm: GluA1, GluA2
Description: GluN1, GluN2A and GluN2B protein levels are reduced in the synaptosomal fraction of cortical tissue from knockin mice compared to wildtype.
Exp Paradigm: GluN1, GluN2A, GluN2B
Description: Neuronal activation in the dorsomedial prefrontal cortex in response to a social stimulus was reduced in the knockin mice compared to wildtype mice. Neuronal activation was measured by calcium signaling in the dorsomedial prefrontal cortex during social interaction. Calcium signaling was measured after injecting AAV-Syn-GCaMP6s into the dmPFC.
Exp Paradigm: AAV-Syn-GCaMP6s injection; partition test
Description: Neuronal activation in knockin mice was reduced after exposure to a novel social partner. Neuronal activation was measured by using a construct that activates Cre recombinase in response to neuronal activation (Fos-driven) and a construct that expresses tdTomato in a Cre-dependent manner. Neuronal activation in the wildtype was higher than the knockin in the prelimbic, infralimbic and anterior cingulate cortices and in the dentate gyrus of the hippocampus.
Exp Paradigm: Fos^2A-iCreER/+ mice crossed with tdTomato reporter mouse line (Ai9): tdTomato and DAPI were visualized; reciprocal social interaction
Description: Knockin mice show decreased social approach in the partition test measured by time in interaction area, distance between subject and partner and duration of each individual approach. Knockin mice show reduction in all parameters.
Description: Knockin mice exhibit a reduced sociability index compared to wildtype mice, indicating that they have a reduced preference ratio for a conspecific partner over an empty cage. Social approach was also measured by time spent near the partner or empty cage, and knockin mice exhibit reduced time in the vicinity of of the partner and increased time in the vicinity of the empty cage compared to control mice. Knockin mice also show reduce time for each individual approach or epoch.
Description: Knockin mice exhibit reduced social interaction measured by time sniffing of conspecific partner versus time sniffing an empty cage. Knockin mice show reduced time sniffing partner and no change in sniffing empty cage, compared to wildtype mice.
Description: Expression of EphB2 protein in almost completely ablated in brain tissue from knockin mice. Decrease is observed in both the immunoprecipitate fraction and total brain lysate.
Description: Expression of Ephb2 mRNA is significantly reduced in knockin mice at 3 and 8 weeks of age. A more substantial decrease in Ephb2 mRNA is observed in the dorsomedial prefrontal cortex in adult mice.
Description: PSD95 protein levels are reduced in the synaptosomal fraction of cortical tissue from knockin mice compared to wildtype.
Exp Paradigm: PSD95
