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Relevance to Autism

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.
Jacobsen syndrome
ASD/autistic features
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
TS
Support
The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Recent Recommendation
PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN816R001 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R002 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R003 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R004 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R005 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R006 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R007 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R008 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R009 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R010 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R011 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R012 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R013 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R014 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R015 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R016 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R017 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R018 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multi-generational 
 GEN816R019 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN816R020 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN816R021 
 missense_variant 
 c.5284C>T 
 p.Arg1762Trp 
 De novo 
  
  
 GEN816R022 
 frameshift_variant 
 c.4713del 
 p.Glu1223LysfsTer22 
 De novo 
  
  
 GEN816R023 
 stop_gained 
 c.714G>A 
 p.Trp238Ter 
 De novo 
  
 Simplex 
 GEN816R024 
 frameshift_variant 
 c.5803dupT 
 p.Leu1935fs 
 Familial 
 Maternal 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Duplication
 1
 
11
Duplication
 1
 
11
Deletion
 5
 
11
Duplication
 1
 
11
Deletion-Duplication
 4
 
11
Deletion
 2
 
11
Deletion
 6
 
11
Deletion-Duplication
 11
 
11
Deletion
 8
 

Model Summary

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.

M_ARHGAP32_1_KO_HM

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

M_ARHGAP32_2_KO_HT

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

M_ARHGAP32_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance1
Decreased
Description: Arhgap32 null mice have decreased latency to fall off the accelerating rotarod compared to wild type controls
Exp Paradigm: Males and females
 Accelerating rotarod test
 8-10 weeks
Clasping reflex1
Increased
Description: Arhgap32 null mice have increased clasping of fore and hind limbs, when suspended by tail, compared to wild type mice
 Tail suspension test
 P21
Miniature post synaptic current amplitude: inhibitory1
Decreased
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
 Whole-cell patch clamp: hippocampal CA1
 6-8 weeks
Self grooming: perseveration1
Increased
Description: Arhgap32 null mice spend significantly more time in repetitive self grooming that controls
Exp Paradigm: Males and females
 Grooming behavior assessments
 8-10 weeks
Repetitive digging1
Increased
Description: Arhgap32 null mice bury significantly more marbles, in a larger area, compared to wild type controls
Exp Paradigm: Males and females
 Marble-burying test
 8-10 weeks
Seizures1
Increased
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
 Observation of chemically induced seizures: kainic acid
 8-10 weeks
Social dominance1
Decreased
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
 Tube test of social dominance
 8-10 weeks
Social scent marking or recognition1
Decreased
Description: Arhgap32 null mice have reduced response to and spend less time interacting with unfamiliar social odors
Exp Paradigm: Males and females
 Olfactory habituation-dishabituation test
 8-10 weeks
Social memory1
Decreased
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
 Three-chamber social approach test
 8-10 weeks
Social interaction1
Decreased
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
 Reciprocal social interaction test
 8-10 weeks
Ultrasonic vocalization: Isolation induced1
Decreased
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
 Monitoring ultrasonic vocalizations
 P7, P10, P14, P21
Cognitive flexibility1
Decreased
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
 Water T-maze test: reversal learning
 8-10 weeks
Olfactory learning and memory1
 No Change
 Olfactory habituation-dishabituation test
 8-10 weeks
Spatial learning1
 No Change
 Water T-maze test
 8-10 weeks
Miniature post synaptic current frequency: inhibitory1
 No Change
 Whole-cell patch clamp: hippocampal CA1
 6-8 weeks
Social approach1
 No Change
 Three-chamber social approach test
 8-10 weeks
 Not Reported: Circadian sleep/wake cycle, Developmental profile, Emotion, Homeostasis, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / Ultrastructure / Cytoarchitecture, Sensory

M_ARHGAP32_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Repetitive digging1
Increased
Description: Arhgap32 hets show increased area and number of marbles buried, compared to WT controls
Exp Paradigm: Males and females
 Marble-burying test
 8-10 weeks
Social interaction1
Decreased
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
 Reciprocal social interaction test
 8-10 weeks
Social dominance1
Decreased
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
 Tube test of social dominance
 8-10 weeks
Ultrasonic vocalization: Isolation induced1
 No Change
 
 P7,P10,P14,P21
Cognitive flexibility1
 No Change
 Water T-maze test: reversal learning
 8-10 weeks
Olfactory learning and memory1
 No Change
 Olfactory habituation-dishabituation test
 8-10 weeks
Spatial learning1
 No Change
 Water T-maze test
 8-10 weeks
Motor coordination and balance1
 No Change
 Accelerating rotarod test
 8-10 weeks
Self grooming: perseveration1
 No Change
 Grooming behavior assessments
 8-10 weeks
Social approach1
 No Change
 Three-chamber social approach test
 8-10 weeks
Social memory1
 No Change
 Three-chamber social approach test
 8-10 weeks
Social scent marking or recognition1
 No Change
 Olfactory habituation-dishabituation test
 8-10 weeks
 Not Reported: Circadian sleep/wake cycle, Developmental profile, Emotion, Homeostasis, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ASB3 ankyrin repeat and SOCS box containing 3 51130 Q9Y575 IP; LC-MS/MS
Huttlin EL , et al. 2015
GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B 2904 Q13224 Y2H; IP/WB; GST
Nakazawa T , et al. 2003
LZTS2 leucine zipper, putative tumor suppressor 2 84445 Q9BRK4 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
Dctn1 dynactin 1 13191 O08788 IP/WB; Co-localization; Rate-zonal centrifugation
Nakamura T , et al. 2016
Gabarap gamma-aminobutyric acid receptor associated protein 56486 Q9DCD6 IP/WB; Co-localization; Rate-zonal centrifugation
Nakamura T , et al. 2016
Gabra1 Gamma-aminobutyric acid receptor subunit alpha-1 14394 P62812 IP/WB; Rate-zonal centrifugation
Nakamura T , et al. 2016
Gabrg2 Gamma-aminobutyric acid receptor subunit gamma-2 14406 P22723 IP/WB; Co-localization; Rate-zonal centrifugation
Nakamura T , et al. 2016
Ywhaq tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide 22630 P68254 IP/WB; Co-localization; Rate-zonal centrifugation
Nakamura T , et al. 2016
Ywhaz tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide 22631 P63101 IP/WB; Co-localization; Rate-zonal centrifugation
Nakamura T , et al. 2016

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