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Relevance to Autism

Maternally-inherited frameshift (A94fs199X) and missense (Y236S and G464R) variants in SYN2 were found to be associated with ASD in male cases (Corradi et al., 2013). Deletion of SYN2 in mice extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming (Greco et al., 2013).

Molecular Function

This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Mutations in this gene may be associated with abnormal presynaptic function and schizophrenia.

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.
ASD
Epilepsy
Positive Association
Association of synapsin 2 with schizophrenia in families of Northern European ancestry.
SCZ
Positive Association
Association study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia.
SCZ
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Recent Recommendation
Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype.
Recent Recommendation
Autism-related behavioral abnormalities in synapsin knockout mice.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN563R001 
 frameshift_variant 
 c.282_288del 
 p.Ala95LeufsTer105 
 Familial 
 Maternal 
 Possible simplex 
 GEN563R002 
 missense_variant 
 c.707A>C 
 p.Tyr236Ser 
 Familial 
 Maternal 
 Possible simplex 
 GEN563R003 
 missense_variant 
 c.1390G>C 
 p.Asp464His 
 Familial 
 Maternal 
 Possible simplex 
 GEN563R004 
 missense_variant 
 c.757C>G 
 p.Pro253Ala 
 Familial 
 Maternal 
 Unknown 
 GEN563R005 
 missense_variant 
 c.557G>A 
 p.Arg186Gln 
 De novo 
 NA 
 Unknown 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion
 6
 
3
Duplication
 1
 
3
Deletion
 1
 
3
Deletion
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 2
 

Model Summary

Syn knockout mice as a useful experimental model of ASD and epilepsy.

References

Type
Title
Author, Year
Primary
Autism-related behavioral abnormalities in synapsin knockout mice.
Additional
The Knockout of Synapsin II in Mice Impairs Social Behavior and Functional Connectivity Generating an ASD-like Phenotype.

M_SYN2_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Synapsin II knockout.
Allele Type:
Strain of Origin:
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Greengard laboratory (PMID 9513186)

M_SYN2_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Synapsin II knockout.
Allele Type:
Strain of Origin:
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Greengard laboratory (PMID 9513186)

M_SYN2_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Righting response2
Decreased
Description: SynII KO pups spent more time to right their body than WT and HET pups.
Exp Paradigm: Frequency and duration of behavioral patterns showed by SynII pups during 3 min of maternal separation was measured.
 Righting reflex test
 P6
Gait2
Decreased
Description: SynII KO mice show an increased frequency of pivoting compared to controls.
 Pivoting test
 P4, 6, 8, 12
Functional magnetic resonance imaging: connectivity2
Decreased
Description: SynII KO male mice showed no change in global connectivity strength compared to controls. SynII KO male mice showed bilateral foci of decreased local connectivity in auditory and somatosensory cortices and intermediate hippocampus in local (short range, <0.6 mm) connectivity mapping compared to WT littermates. Local connectivity in auditory areas and intermediate hippocampus correlated with USV calls impairment in individual subjects. SynII KO male mice showed reduced inter-hemispheric connectivity between the auditory cortex and its homotopic contralateral regions compared to controls. SynII KO male mice showed no change in inter-hemispheric connectivity between homologous brain regions in the insular cortex, primary motor cortex, somatosensory cortex, and
Exp Paradigm: To identify macroscale functional substrates involved in the behavioral alterations local and long-range connectivity was mapped using rsfMRI. Mice were under shallow halothane anesthesia.
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Circling2
Decreased
Description: SynII KO mice show decreased frequency and duration of circling compared to controls.
 Home cage behavior
 P4, 6, 8, 12
Self grooming: perseveration2
Increased
Description: SynII KO mice spend more time self grooming than controls.
 Grooming behavior assessments
 Adult
Repetitive digging1
Decreased
Description: Decreased marble burying behavior indicative of decreased environmental interest
Exp Paradigm: Marble-burying test
 Marble-burying test
 6 months
Social dominance1
Increased
Description: Increased social dominance as indicated by higher percentage of matches won
Exp Paradigm: Social dominance tube test
 Tube test of social dominance
 2, 6 months
Social interaction: opposite sex2
Decreased
Description: SynII KO male mice spent less time investigating a C57BL/6J female partner than WT mice. SynII KO male mice approached a receptice C57BL/6J female partner with less frequency than WT mice.
Exp Paradigm: Total sniffing time was measured.
 Reciprocal social interaction test
 Adult
Aggression1
Decreased
Description: Decreased aggression indicated by reduced social interaction with intruder after 1-2 months of social isolation
Exp Paradigm: Resident intruder test
 Resident-intruder test
 6 months
Social interaction1
Decreased
Description: Decreased social novelty indicated by failure to discirminate between familiar vs. novel mouse
Exp Paradigm: Social novelty phase of three-chambered social approach test
 Three-chamber social approach test
 2, 6 months
Social interaction1
Decreased
Description: Decreased sociability indicated by reduced interest in both cups
Exp Paradigm: Three-chamber social approach test
 Three-chamber social approach test
 2 months
Social memory1
Decreased
Description: Decreased social recognition indicated by failure to increased exploration of novel vs. intruder mouse
Exp Paradigm: Social recognition test
 Social recognition test
 2, 6 months
Ultrasonic vocalization: isolation induced2
Decreased
Description: Synapsin II homozygous knockout pups separated from their mothers show decrease in the number of calls per minute, in the total duration of the calls, but no change in the categories of calls emitted, compared to controls.
Exp Paradigm: 3-min maternal separation test. Peak frequency, amplitude and total duration of the call were measured. Call categories were analyzed: Cx=complex, Tc=two-component, Up=upward, Dw=downward, Ch=chevron, Sh=short, Cp=composite, Fs=frequency steps, Fl=flat, Un=unstructured.
 Monitoring ultrasonic vocalizations
 P4, P6, P8, P12
Ultrasonic vocalization: interaction induced: opposite sex stimulus2
Decreased
Description: Adult synapsin II homozygous male mice show changes in various categories (Cx, Tc, Up, Dw, Fs) of calls emited during courtship compared to controls. Adult synapsin II homozygous male mice show reduction in the duration of calls during courtship compared to controls.
Exp Paradigm: 3-min maternal separation test. Peak frequency, amplitude and total duration of the call were measured. Call categories were analyzed: Cx=complex, Tc=two-component, Up=upward, Dw=downward, Ch=chevron, Sh=short, Cp=composite, Fs=frequency steps, Fl=flat, Un=unstructured.
 Monitoring ultrasonic vocalizations
 Adult
Anxiety1
 No change
 Light-dark exploration test
 2, 6 months
General locomotor activity1
 No change
 Open field test
 2, 6 months
Righting response2
 No change
 Righting reflex test
 P4,8,12
Brain morphology2
 No change
 Voxel based morphometry
 3- dimensional volumetric assessment of cortical and subcortical structures.
Brain size2
 No change
 Voxel based morphometry
 
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 2, 6 months
Olfaction1
 No change
 Buried food test
 2, 6 months
Social interaction1
 No change
 Social transmission of food preference
 2, 6 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure, Sensory

M_SYN2_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
 No change
 Monitoring ultrasonic vocalizations
 Adult
Ultrasonic vocalization: isolation induced1
 No change
 Monitoring ultrasonic vocalizations
 P4, P6, P8, P12
Gait1
 No change
 Pivoting test
 P4, 6, 8, 12
Righting response1
 No change
 Righting reflex test
 P4,6,8,12
Brain morphology1
 No change
 Voxel based morphometry
 3- dimensional volumetric assessment of cortical and subcortical structures.
Brain size1
 No change
 Voxel based morphometry
 
Circling1
 No change
 Home cage behavior
 P4, 6, 8, 12
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 Adult
Social interaction: opposite sex1
 No change
 Reciprocal social interaction test
 Adult
 Not Reported: Circadian sleep/wake cycle, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Neurophysiology, Physiological parameters, Seizure, Sensory

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