Rare variants and deletions have been identified in AUTS2 in individuals with ASD and other neurodevelopmental disorders (NDD) in multiple studies. While initial studies were performed without rigorous comparison with controls, Beunders et al., 2013 demonstrated a statistical enrichment of exonic AUTS2 deletions in NDD cases compared to controls (24/49,684 cases vs. 0/16,784 controls; P=0.00092). In addition to ASD, there is genetic evidence implicating it in developmental delay/intellectual disability, epilepsy and ADHD. Knockdown of AUTS2 in zebrafish resulted in smaller head size, neuronal reduction, and decreased mobility (Oksenberg et al., 2013), while knockdown in mice led to impaired cortical neuronal migration and neuritogenesis (Hori et al., 2014). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified AUTS2 as a gene reaching exome-wide significance (P < 2.5E-06); association of AUTS2 with ASD risk in this analysis was found to be driven both by de novo variants (in particular, de novo loss-of-function variants in six ASD probands from the SPARK cohort) and rare inherited loss-of-function variants transmitted from unaffected parents to affected offspring.
Molecular Function
Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.In the cytoplasm, plays a role in axon and dendrite elongation and in neuronal migration during embryonic brain development. Promotes reorganization of the actin cytoskeleton, lamellipodia formation and neurite elongation via its interaction with RAC guanine nucleotide exchange factors, which then leads to the activation of RAC1.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins.
Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenot
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies
Isolated loss of the AUTS2 long isoform, brain-wide or targeted to Calbindin-lineage cells, generates a specific suite of brain, behavioral, and molecular pathologies
The conditional knock out ( both homozygous and heterozygous) mice, with Auts2 knocked out only in the brain, show reduced growth and size compared to wild type littermate controls and also display other anomalies during early development like, reduced instances of ultrasonic vocalizations and poor righting reflex.
References
Type
Title
Author, Year
Primary
An AUTS2-Polycomb complex activates gene expression in the CNS.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 7 of the Auts2 using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional deletion of exon 7 of the Auts2 using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system, bred to homozygosity
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57Bl/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
A loxp site was inserted upstream of exon 8 and a loxp site and a frt-flanked neomycin cassette were inserted downstream of exon 8 in opposite orientation. cre-mediated recombination removed exon 8 and the selection cassette in germline. the full-length protein is completely eliminated in homozygous brain, however expression of a short isoform (variant 2 with transcriptional start site in exon 9) is increased. (auts2^del8/del8)
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
A loxp site was inserted upstream of exon 8 and a loxp site and a frt-flanked neomycin cassette were inserted downstream of exon 8 in opposite orientation. immunohistochemistry indicates that both the full-length and shorter splicing variant (variant 1 with transcriptional start site in exon 7) proteins are almost completely eliminated in the brain of homozygotes. (auts2^neo/+)
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Mouse model of acute ko of austs2 at e14.5 was generated by electroporating cortical brain sections of auts2flox/flox mice with gfp and/or cre recombinase
Allele Type: Conditional knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Deletion of exon 8 of auts2
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Wildtype
Mutation:
Shrna constructs targeting fl-auts2 mrna and gfp expression vectors were cointroduced into mouse embryonic brains by in utero electroporation at e15.5, and dissociated cortical neurons were prepared at e16.5 and cultured for div2 to div6. co-electroporation and expression of the shrna-resistant auts2 (fl-auts2r) was used as control.
Allele Type: Wildtype
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Wildtype
Mutation:
Shrna constructs targeting fl-auts2 mrna and gfp expression vectors were cointroduced into mouse embryonic cerebral cortices by in utero electroporation at e14.5. co-electroporation and expression of the shrna-resistant auts2 (fl-auts2r) and shrna-resistant cytoplastically localized auts2 (nes-fl-auts2r) were used as control.
Allele Type: Wildtype
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
A loxp site was inserted upstream of exon 8 and a loxp site and a frt-flanked neomycin cassette were inserted downstream of exon 8 in opposite orientation. immunohistochemistry indicates that both the full-length and shorter splicing variant (variant 1 with transcriptional start site in exon 7) proteins are almost completely eliminated in the brain of homozygotes. (auts2^neo/neo)
Allele Type: Knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Forebrain-specific auts2 conditional ko mice (emx1cre/+;auts2-ex8^flox/flox) generated by crossing conditional-ready mice with exon 8 of auts2 floxed and emx1cre mice
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Forebrain-specific auts2 conditional ko mice (emx1cre/+;auts2flox/flox) generated by crossing conditional-ready mice with exon 8 of auts2 floxed and emx1cre mice
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Camkiia-creert2 mice on a mixed c57bl6n/fvb background were crossed with auts2 floxed mice to generate camkiia-creert2;auts2^flox/+ mice which were in turn crossed to generate camkiia-creert2;auts2^flox/flox mice.tamoxifen was administered at 50 mg/kg during p21-25 days for anatomical analysis at p50. rosa26ryfp reporter allele was used to confirm cre recombination.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Camkiia-creert2 mice on a mixed c57bl6n/fvb background were crossed with auts2 floxed mice to generate camkiia-creert2;auts2^flox/+ mice which were in turn crossed to generate camkiia-creert2;auts2^flox/flox mice in which exon 8 of auts2 can be ablated in the forebrain projection neurons by tamoxifen administration. tamoxifen was administered at p30-34 for behavioral analyses by intraperitoneal injection twice daily for 5 consecutive days and the analyses were performed at 10-12 weeks.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Cerebellum-selective auts2 conditional knockout (cko) mice were generated by crossing auts2 exon-8 floxed mice with engrailed1-cre mice leading to complete loss of full length and c-terminal shortform variant1 of auts2 and concomittant increase in c-terminal short isoform variant 2, in the rhombomere-1-derived brain area including the cerebellum from mid-embryonic stages (e9.5)
Allele Type: Conditional knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Hori et al., 2014; Kimmel et al., 2000; The Jackson Laboratory
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Cerebellum-selective auts2 conditional knockout (cko) mice were generated by crossing auts2 exon-8 floxed mice with engrailed1-cre mice leading to complete loss of full length and c-terminal shortform variant1 of auts2 and concomittant increase in c-terminal short isoform variant 2, in the rhombomere-1-derived brain area including the cerebellum from mid-embryonic stages (e9.5)
Allele Type: Conditional knockout
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Hori et al., 2014; Kimmel et al., 2000; The Jackson Laboratory
Model Type:
Genetic LOF
Model Genotype:
Wildtype
Mutation:
Pregnant c57bl/6 mice at e11.5 or e12.5 and plasmids were injected into the fourth ventricle with a vector expressing egfp and auts2-targeted microrna (mirna) driven by the pc-specific l7 promoter into pcs by in utero electroporation.
Allele Type: Wildtype
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Yamashiro et al, 2020
Description: Auts2 ko mice show impaired righting reflex as they took longer to place all four paws on the ground after being initially placed on their backs
Exp Paradigm: NA
Description: Auts2 ko mice show reduced emissions of ultrasonic vocalizations following maternal separation compared to wild type littermates
Exp Paradigm: NA
Description: Auts2 ko mice show significantly reduced body weight compared to wildtype littermates which was not entirely correlated with amount of milk ingestion at p1
Exp Paradigm: NA
Description: Auts2 ko mice show impaired righting reflex as they took longer to place all four paws on the ground after being initially placed on their backs
Exp Paradigm: NA
Description: Auts2 ko mice show reduced emissions of ultrasonic vocalizations following maternal separation compared to wild type littermates
Exp Paradigm: NA
Description: Auts2 ko mice show significantly reduced body weight compared to wildtype littermates, hets show intermediate phenotype between wild type and homozygous knockouts which was not entirely correlated with amount of milk ingestion at p1 as het mice have similar milk bands at that age to wild types
Exp Paradigm: NA
Description: Severe impairment of axonal alongation in contralateral projecting axons of layer ii/iii cortical neurons of embryos electroporated with gfp at e14.5
Description: Severe impairment of axonal alongation in contralateral projecting axons of layer ii/iii cortical neurons of embryos electroporated with gfp at e14.5
Description: Increase in both mature â??â??mushroomâ??â?? spines and immature â??â??thinâ??â?? spines, indicating auts2 does not affect spine maturation
Description: Severe impairment of axonal alongation in contralateral projecting axons of layer ii/iii cortical neurons of embryos electroporated with gfp at e14.5
Description: Decrease in numbers of the complicated syllable type, including â??â??harmonics,â??â?? â??â??complex,â??â?? or â??â??one jump + harmonics,â??â?? and increase in the simple syllable types with shorter duration such as â??â??downwardâ??â?? or â??â??shortâ??â??
Description: Increased excitatory presynaptic marker vglut1 in the mpfc but not inhibitory vgat-labeled puncta at mpfc was increased
Exp Paradigm: vglut1
Description: Increase in both mature â??â??mushroomâ??â?? spines and immature â??â??thinâ??â?? spines, indicating auts2 does not affect spine maturation
Description: Spines density increased on the secondary dendrites of layer ii/iii pyramidal neurons in the medial prefrontal cortex, on secondary dendritic segments along apical dendrites of hippocampal ca1 pyramidal neurons and dendrites of the upper-layer neurons of the auditory cortex; aberrant spine formation along primary apical dendrites immediately proximal to the cell soma of ca1 hippocampal pyramidal neurons as well as cortical layer ii/iii neuron; no change in spine densities on basal dendrites of ca1 pyramidal
Description: Differential gene expression of 168 genes in the hippocampus, with 78 downregulated and 90 upregulated genes, including reln, mdga1, camk2b, cacna1c, and c1ql-family genes associated with nervous system development, cell differentiation, neuronal migration, dendritic spine morphogenesis, negative regulation of synapse assembly, regulation of cytosolic calcium ion concentration, membrane genes and synapse genes; mdga1, camk2b, and sema6b were upregulated; dcc, gfra1, gpc2, hap1 were downregulated
Description: Absence of auts2 protein full-length isoform and s-suts2 var1 isoform, increased protein level of s-auts2 var.2; differential splice isoform expression; compensatory expression
Description: Spines density increased on the secondary dendrites of layer ii/iii pyramidal neurons in the medial prefrontal cortex, on secondary dendritic segments along apical dendrites of hippocampal ca1 pyramidal neurons and dendrites of the upper-layer neurons of the auditory cortex; aberrant spine formation along primary apical dendrites immediately proximal to the cell soma of ca1 hippocampal pyramidal neurons as well as cortical layer ii/iii neuron; no change in spine densities on basal dendrites of ca1 pyramidal
Description: Increase in both mature â??â??mushroomâ??â?? spines and immature â??â??thinâ??â?? spines, indicating auts2 does not affect spine maturation
Description: Increase in both mature â??â??mushroomâ??â?? spines and immature â??â??thinâ??â?? spines, indicating auts2 does not affect spine maturation
Description: Most purkinje cells appear immature stellate cell-like in shape with more than 2 perisomatic dendrites at p7 and p10; impaired pruning of pc dendrites
Exp Paradigm: Clb
Description: Smaller and deformed cerebella; aberrant cerebellar cortical morphologies; cerebellar lobules including lobe x, crus i, and copula pyramidis were reduced in size or absent; no change in lamination
Description: About 50% pcs receive multiple climbing fiber inputs while most pcs in wt mature cerebellum show a single-step response to an evoked cf input, indicating that the majority of pcs receive a single cf input; no change in disparity ratio and index
