Association has been found between the ASTN2 gene and autism. Glessner et al. (2009) identified a rare ASTN2 deletion in an autism case. Another study found a link between rare ASTN2 CNVs and schizophrenia.
Molecular Function
This gene encodes a protein that is expressed in the brain and may function in neuronal migration, based on functional studies of the related astrotactin 1 gene in human and mouse. A deletion at this locus has been associated with schizophrenia.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
Unveiling Hidden Genetic Architectures: Molecular Diagnostic Yield of Whole Exome Sequencing in 50 Children With Autism Spectrum Disorder Negative for Copy Number Variations
ASTN2 heterozygous deletion has deficits in isolation-induced ultrasonic vocalization, but no changes in hyperactivity, repetitive behaviors or anxiety. Homozygous knockout mice for this gene are viable and healthy, but have more ASD-associated phenotypes than the heterozygous model, including more prominent deficits in ultrasonic vocalizations, hyperactivity, repetitive behaviors, anxiety, social memory and eye blink conditioning. A model with a targeted deletion of ASTN2 in Purkinje cells retains repetitive behaviors and hyperactivity phenotypes. Knockout mice show changes in cerebellar glial morphology, and changes in spontaneous and evoked synaptic transmission from parallel fibers to Purkinje cells.
References
Type
Title
Author, Year
Primary
Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
C57BL/6J mice were used to create the Astn2 knockout allele. To knock out Astn2, two guide RNAs flanking the promoter and the exon containing ATG start codon were selected. RNP containing guide RNA and cas9 protein were co-injected into C57BL/6 fertilized embryos.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Mary E. Hatten (Rockefeller University)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
C57BL/6J mice were used to create the Astn2 knockout allele. To knock out Astn2, two guide RNAs flanking the promoter and the exon containing ATG start codon were selected. RNP containing guide RNA and cas9 protein were co-injected into C57BL/6 fertilized embryos.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Mary E. Hatten (Rockefeller University)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To generate the Astn2^flox allele, two sgRNAs targeting the exon containing ATG start codon were constructed. A donor plasmid containing the exon flanked by two loxP sites and two homology arms of 800 bp each was also constructed. RNP containing two sgRNAs and Cas9 protein were co-injected into C57BL/6 fertilized embryos. The Pcp2-Cre transgene (MGI:3836637) contains a Cre-expression cassette with the Cre recombinase under the control of the Pcp2 promoter, which is crossed to Astn2^flox/flox mice to generate a Purkinje cell-specific conditional knockout line.
Allele Type: Conditional knockout
Strain of Origin: C57BL/6J; FVB/N
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Mary E. Hatten (Rockefeller University); GENSAT Project (Rockefeller University)
Description: Knockout mice display a significant difference in the distributions of spine lengths. A closer look at the spine length distributions revealed a significant decrease in the fraction of long, filopodia-like spines in knockout animals compared to wildtype.
Description: Knockout mice display a significant increase in the antibody signal for GFAP as well as apparent disorganization of Bergmann glia radial fibers that span the molecular layer.
Exp Paradigm: GFAP
Spontaneous post synaptic event amplitude: excitatory currents1
Increased
Description: Knockout mice display an increase in amplitude of sEPSCs compared to wildtype mice. The difference is more pronounced in the posterior vermis but present also in the anterior vermis.
Exp Paradigm: Cerebellum
Spontaneous post synaptic event frequency: inhibitory currents1
Decreased
Description: Knockout mice display a small but significant decrease in frequency of sEPSCs in the posterior vermis compared to wildtype mice. The decrease was not significant in the anterior vermis.
Exp Paradigm: Cerebellum
Spontaneous post synaptic event frequency: excitatory currents1
Decreased
Description: Knockout mice display a decrease in frequency of sEPSCs compared to wildtype mice. The difference is more pronounced in the posterior vermis but present also in the anterior vermis.
Exp Paradigm: Cerebellum
Spontaneous post synaptic event amplitude: inhibitory currents1
Increased
Description: Knockout mice display an increase in amplitude of sIPSCs compared to wildtype mice. The difference is more pronounced in the posterior vermis but present also in the anterior vermis.
Exp Paradigm: Cerebellum
Description: Knockout mice display an increase in amplitude of evoked EPSCs. The difference is more pronounced in the posterior vermis but present also in the anterior vermis.
Exp Paradigm: Cerebellum
Description: Knockout mice, unlike wildtype mice, did not show a preference for the novel mouse and spent similar amount of time investigating the novel and the familiar counterparts.
Description: Knockout mice exhibited significantly fewer USVs at ages P6-P10 during the 5-minute recording session. Knockout mice also produced fewer bouts of calls compared to heterozygous and wildtype littermates on days P6â??P10. Knockout mice exhibited longer pauses between calls within a bout, shorter individual calls, a narrowing of frequency pitch range and a decrease in the fraction of dynamic calls compared to wildtype and heterozygous littermates.
Description: Knockout mice did not show a preference for the dark compartment but had significantly lower latency to enter the light compartment compared to wildtype littermates.
Description: Knockout mice show a trend toward reduced learning relative to wildtype mice, with a decrease in CR probability and amplitude at later learning timepoints. Notably, all wildtype animals exhibited learning, five of nine knockout animals exhibited little or no learning.
Description: Translating ribosome affinity purification followed by RNA sequencing was used to examine changes in gene expression after the loss of ASTN2. Differential analysis revealed only four differentially expressed genes in Purkinje cells, including Astn2 and Trim32. Notably, the expression of Astn1 mRNA was not changed.
Description: Proteomic analysis of knockout mice revealed that ASTN2 protein is highly reduced, as expected, TRIM32 shows a significant increase in protein levels, RASSF8 is slightly reduced, and the protein levels of ASTN1 are increased around twofold.
Exp Paradigm: Cerebellum
Description: Heterozygous mice exhibited significantly fewer USVs at ages P6-P8 during the 5-minute recording session. Heterozygous pups showed an intermediate phenotype with reduced bouts only on day P8.
