Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016).
Molecular Function
RICS, the protein encoded by the ARHGAP32 gene, is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulating Rho GTPase.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q.
Arhgap32 null mice have impaired social behavior displaying reduced social memory and inclination towards reciprocal social interaction, along with reduced social dominance. They show increased repetitive behavior with increase in self-grooming and repetitive digging. Arhgap32 null pups also make fewer ultrasonic calls upon isolation from the mother. Additionally, motor coordination and flexibility in learning new goals are also reduced in the null mice. In neuronal cultures Arhgap32 null neurons have reduced expression of GABAa receptors on the surface.
References
Type
Title
Author, Year
Primary
PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The targeting vector replaced the start codon of Arhgap32 gene with a lacZ-neo cassette using homologous recombination. After germline transmission the knockout mice were bred to homozygosity and maintained or backcrossed to the C57BL/6N background for 10 generations.
Allele Type: Targeted(knockout)
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: TT2
Mutant ES Cell Line: Model Source: Nasu- Nishimara et al Genes Cells 2006
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The targeting vector replaced the start codon of Arhgap32 gene with a lacZ-neo cassette using homologouz recombination. After germline transmission the knockout mice were backcrossed to C57BL/6N background.
Allele Type: Targeted(knockout)
Strain of Origin: Genetic Background: C57BL/6N
ES Cell Line: TT2
Mutant ES Cell Line: Model Source: Nasu- Nishimara et al Genes Cells 2006
Description: Arhgap32 null mice have decreased latency to fall off the accelerating rotarod compared to wild type controls
Exp Paradigm: Males and females
Description: Mipsc amplitude is significantly reduced in the hippocampal ca1 region in arhgap32 mice, authors state that this indicates attenuation of post synaptic responsiveness
Exp Paradigm: Males and females
Description: Arhgap32 null mice have significantly more seizures with a lower latency to progress to the next level of seizures, that wild type mice, both groups are tested after injection with kainic acid
Exp Paradigm: Males and females
Description: Arhgap32 null mice have no preference a novel stranger mouse over a familiar mouse in the three chamber test, unlike wild type controls
Exp Paradigm: Males and females
Description: Arhgap32 null mice avoid social interaction and spent less time in nose to nose sniffing, huddling etc in the reciprocal social interaction test in an open area
Exp Paradigm: Males and females
Description: In the tube test for social dominance arhgap32 mice rarely won against wt controls and also won significantly less number of times against hets
Exp Paradigm: Males and females
Description: Arhgap32 null pups have a reduced frequency of emitting usvs and a longer latency to emit the first call upon separation from mother, this is statistically significant at p10, p14
Exp Paradigm: Males and females
Description: Arhgap32 null mice have significantly reduced cognitive flexibility assessed by reversal learning in the water t-maze where they continue to use previously acquired memory for making a choice
Exp Paradigm: Males and females
Description: Arhgap32 hets show reduced social dominance, with significantly reduced 'winning rate' compared to wt controls in the tube test, authors have reported that compared to arhgap32 null mice, arhgap32 hets have a higher winning rate
Exp Paradigm: Males and females
Description: Arhgap32 hets spend reduced amount of time in social interaction, nose-nose sniffing, huddling etc, in reciprocal social interaction test, compared to wt controls
Exp Paradigm: Males and females
