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Relevance to Autism

Several studies have identified rare mutations in the SHANK2 gene in autistic and intellectually disabled individuals (Berkel et al., 2010; Pinto et al., 2010; Leblond et al., 2012; Sanders et al., 2012). A functional study analyzed three of the mutations previously found in individuals with ASD (L1008_P1009dup, T1127M and R462X). The mutations were found to have varying effects on protein localization, dendritic spine volume and branching in cultured neurons and even synaptic transmission and cognitive behavior in mice, with the R462X variant causing the most severe phenotypes (Berkel et al., 2012).

Molecular Function

Shank proteins contain multiple domains for protein-protein interactions and function as molecular scaffolds in the postsynaptic density (PSD).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.
ASD
MR
Positive Association
Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder.
ASD
Negative Association
Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.
ASD
Support
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.
ID
Epilepsy, ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
ASD
Support
Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.
ASD
Support
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
ASD
Support
Genome-wide characteristics of de novo mutations in autism.
ASD
Support
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...
ASD
Support
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
ASD
ID
Support
Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness.
SCZ
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Functional impact of global rare copy number variation in autism spectrum disorders.
ASD
Support
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci.
DD, ID
Support
Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluo...
ASD, OCD
Support
Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangemen...
DD, ID
Autistic behavior
Support
A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders.
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ID, ADHD
Highly Cited
Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.
Highly Cited
The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal.
Highly Cited
The Shank family of scaffold proteins.
Recent Recommendation
Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology.
ASD
ID
Recent Recommendation
SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons.
ASD
Recent Recommendation
Activity induced changes in the distribution of Shanks at hippocampal synapses.
Recent Recommendation
Effect of the autism-associated lncRNA Shank2-AS on architecture and growth of neurons.
Recent Recommendation
BetaPix up-regulates Na? exchanger 3 through a Shank2-mediated protein-protein interaction.
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
AnkyrinG is required to maintain axo-dendritic polarity in vivo.
Recent Recommendation
Identification and functional characterization of rare SHANK2 variants in schizophrenia.
SCZ
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Recent Recommendation
Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN229R001 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN229R002 
 stop_gained 
 c.1384C>T 
 p.Arg462Ter 
 De novo 
  
 Simplex 
 GEN229R003 
 missense_variant 
 c.76C>T 
 p.Arg26Trp 
 Familial 
 Paternal 
  
 GEN229R004 
 missense_variant 
 c.622C>T 
 p.Pro208Ser 
 Familial 
 Maternal 
 Multiplex 
 GEN229R005 
 inframe_insertion 
 c.3024_3029dup 
 p.Leu1008_Pro1009dup2 
 Familial 
 Maternal 
  
 GEN229R006 
 missense_variant 
 c.3380C>T 
 p.Thr1127Met 
 Familial 
 Maternal 
  
 GEN229R007 
 missense_variant 
 c.4048G>A 
 p.Ala1350Thr 
 Familial 
 Maternal 
 Multiplex 
 GEN229R008 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN229R009 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN229R010 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN229R011 
 missense_variant 
 c.1327C>T 
 p.Arg443Cys 
  
  
  
 GEN229R012 
 missense_variant 
 C>A 
 p.Arg598Leu 
  
  
  
 GEN229R013 
 missense_variant 
 c.2149G>T 
 p.Val717Phe 
 Familial 
 Paternal 
 Simplex 
 GEN229R014 
 missense_variant 
 C>T 
 p.Ala729Thr 
 Familial 
 Maternal 
 Multiplex 
 GEN229R015 
 missense_variant 
 c.3484G>A 
 p.Glu1162Lys 
  
  
  
 GEN229R016 
 missense_variant 
 C>T 
 p.Gly1170Arg 
 Familial 
 Maternal 
 Simplex 
 GEN229R017 
 missense_variant 
 c.4126G>A 
 p.Val1376Ile 
  
  
  
 GEN229R018 
 missense_variant 
 c.4605A>T 
 p.Asp1535Asn 
 Familial 
 Maternal 
 Simplex 
 GEN229R019 
 missense_variant 
 A>G 
 p.Leu1722Pro 
 Familial 
 Paternal 
 Simplex 
 GEN229R020 
 missense_variant 
 G>A 
 p.Thr410Met 
  
  
  
 GEN229R021 
 missense_variant 
 C>T 
 p.Ser557Asn 
  
  
  
 GEN229R022 
 missense_variant 
 C>T 
 p.Met1717Ile 
  
  
  
 GEN229R023 
 missense_variant 
 c.467A>G 
 p.Lys156Arg 
  
  
  
 GEN229R024 
 synonymous_variant 
 c.492C>T 
 p.(=) 
  
  
  
 GEN229R025 
 intron_variant 
 c.526+61G>A 
 N/A 
  
  
  
 GEN229R026 
 intron_variant 
 c.527-18C>A 
 N/A 
  
  
  
 GEN229R027 
 intron_variant 
 c.527-8G>T 
 N/A 
  
  
  
 GEN229R028 
 missense_variant 
 c.569G>A 
 p.Arg190His 
  
  
  
 GEN229R029 
 intron_variant 
 c.640+11C>T 
 N/A 
  
  
  
 GEN229R030 
 intron_variant 
 c.800-33C>T 
 N/A 
  
  
  
 GEN229R031 
 intron_variant 
 c.924+19G>A 
 N/A 
  
  
  
 GEN229R032 
 intron_variant 
 c.924+133G>C 
 N/A 
  
  
  
 GEN229R033 
 intron_variant 
 c.1061-81C>T 
 N/A 
  
  
  
 GEN229R034 
 intron_variant 
 c.1141+49G>A 
 N/A 
  
  
  
 GEN229R035 
 intron_variant 
 c.1148-109C>T 
 N/A 
  
  
  
 GEN229R036 
 missense_variant 
 c.1201A>C 
 p.Lys401Gln 
  
  
  
 GEN229R037 
 synonymous_variant 
 c.1284G>A 
 p.(=) 
  
  
  
 GEN229R038 
 intron_variant 
 c.302+14C>A 
 N/A 
  
  
  
 GEN229R039 
 intron_variant 
 c.1302+35G>A 
 N/A 
  
  
  
 GEN229R040 
 intron_variant 
 c.1303-54C>T 
 N/A 
  
  
  
 GEN229R041 
 missense_variant 
 c.1316G>A 
 p.Arg439His 
  
  
  
 GEN229R042 
 synonymous_variant 
 c.1392G>T 
 p.(=) 
  
  
  
 GEN229R043 
 missense_variant 
 c.1763A>G 
 p.Tyr588Cys 
  
  
  
 GEN229R044 
 synonymous_variant 
 c.1923G>A 
 p.(=) 
  
  
  
 GEN229R045 
 synonymous_variant 
 c.2052G>A 
 p.(=) 
  
  
  
 GEN229R046 
 synonymous_variant 
 c.2823C>T 
 p.(=) 
  
  
  
 GEN229R047 
 synonymous_variant 
 c.3135C>T 
 p.(=) 
  
  
  
 GEN229R048 
 synonymous_variant 
 c.3324C>T 
 p.(=) 
  
  
  
 GEN229R049 
 missense_variant 
 c.3620C>T 
 p.Pro1207Leu 
  
  
  
 GEN229R050 
 intron_variant 
 c.3843-12T>C 
 N/A 
  
  
  
 GEN229R051 
 frameshift_variant 
 c.2542insCA 
  
 De novo 
  
 Simplex 
 GEN229R052 
 synonymous_variant 
 c.132G>A 
 p.(=) 
 De novo 
  
 Simplex 
 GEN229R053 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN229R054 
 inversion 
  
  
 De novo 
  
 Simplex 
 GEN229R055 
 translocation 
  
  
 De novo 
  
  
 GEN229R056 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN229R057 
 translocation 
  
  
 De novo 
  
  
 GEN229R058 
 nonsynonymous_variant 
  
  
 Unknown 
  
 Unknown 
 GEN229R059 
 missense_variant 
 c.1313C>T 
 p.Thr438Met 
 Familial 
 Maternal 
  
 GEN229R060 
 missense_variant 
 C>A 
 p.Gly488Val 
 Unknown 
  
  
 GEN229R061 
 missense_variant 
 c.1829C>A 
 p.Ser610Tyr 
 Unknown 
  
  
 GEN229R062 
 missense_variant 
 c.2069A>G 
 p.Asn690Ser 
 Unknown 
  
  
 GEN229R063 
 missense_variant 
 c.2872C>A 
 p.Arg958Ser 
 Unknown 
  
  
 GEN229R064 
 missense_variant 
 c.3355C>A 
 p.Pro1119Thr 
 Unknown 
  
  
 GEN229R065 
 missense_variant 
 c.3431C>T 
 p.Pro1144Leu 
 Familial 
 Maternal 
  
 GEN229R066 
 missense_variant 
 c.4822G>A 
 p.Val1608Ile 
 Familial 
 Maternal 
  
 GEN229R067 
 missense_variant 
 c.4936C>A 
 p.Leu1646Met 
 Familial 
 Maternal 
  
 GEN229R068 
 missense_variant 
 c.5191G>T 
 p.Ala1731Ser 
 Familial (n=2), unknown (n=2) 
 Maternal (n=2) 
  
 GEN229R069 
 missense_variant 
  
 p.Ala578Val 
 Familial 
 Maternal 
 Multiplex 
 GEN229R070 
 stop_gained 
 c.757C>T 
 p.Arg253Ter 
 De novo 
  
 Simplex 
 GEN229R071 
 missense_variant 
 c.3427G>A 
 p.Ala1143Thr 
 De novo 
  
 Simplex 
 GEN229R072 
 frameshift_variant 
 c.1896dupA 
 p.Asp633Argfs 
 De novo 
  
  
 GEN229R073 
 missense_variant 
 c.2518C>T 
 p.Pro840Ser 
 Familial 
 Paternal 
  
 GEN229R074 
 stop_gained 
 c.87C>G 
 p.Tyr29Ter 
 De novo 
  
 Simplex 
 GEN229R075 
 missense_variant 
 c.359C>T 
 p.Arg120Gln 
 Familial 
 Maternal 
 Simplex 
 GEN229R076 
 frameshift_variant 
 c.2540_2541del 
 p.Ser847Ter 
 De novo 
  
  
 GEN229R077 
 missense_variant 
 C>T 
 p.Glu11Lys 
 Unknown 
  
 Multiplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN229C001 
 intron_variant 
 rs76717360 
 c.2062-22283G>A;c.298-22283G>A 
  
 226 Chinese ASD cases (188 male, 38 female) and 239 Chinese controls without ASD or other psychiatric disorders (193 males, 46 females) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion
 2
 
11
Deletion
 7
 
11
Duplication
 4
 
11
Deletion-Duplication
 15
 

Model Summary

Shank2 knockout rats exhibit decreased social behaviors and increased repetitive behaviors.

References

Type
Title
Author, Year
Primary
Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism.

R_SHANK2_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: ZFN targeted to exon 31 of Shank2, targeting PDZ domain
Allele Type: Knockout
Strain of Origin: Sprague Dawley
Genetic Background: Sprague Dawley
ES Cell Line:
Mutant ES Cell Line:
Model Source: SAGE Labs

R_SHANK2_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: ZFN targeted to exon 31 of Shank2, targeting PDZ domain
Allele Type: Knockout
Strain of Origin: Sprague Dawley
Genetic Background: Sprague Dawley
ES Cell Line:
Mutant ES Cell Line:
Model Source: SAGE Labs

R_SHANK2_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: Ambulatory activity1
Increased
Description: Increased distance travelled
 Open field test
 2-3 months
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Decreased dendritic branching in hippocampus
 Sholl analysis: Golgi-Cox staining
 Unreported
Neuronal size1
Increased
Description: Increased neuronal soma size in striatum
 Golgi-Cox staining
 Unreported
Neuronal size1
Decreased
Description: Decreased neuronal soma size in hippocampus
 Golgi-Cox staining
 Unreported
Dendritic architecture: dendritic tree complexity1
Increased
Description: Increased dendritic brancing in striatum
 Sholl analysis: Golgi-Cox staining
 Unreported
Synaptic plasticity: hippocampal LTP1
Decreased
Description: Decreased hippocampal LTP in response to theta-burst stimulation
 Field potential recordings
 Unreported
Synaptic plasticity: hippocampal LTD1
Decreased
Description: Absent hippocampal LTD in response to low frequency stimulation
 Field potential recordings
 Unreported
Synaptic neuroreceptor ratio (NMDAR/AMPAR) dependent transmission1
Increased
Description: Increase in NMDA current amplitude, with no change in AMPA current amplitude
 Field potential recordings
 Unreported
Synaptic plasticity: striatal LTD1
Increased
Description: Increase in striatal LTD response
 Field potential recordings
 Unreported
Event related oscillations (EROs) in electroencephalography (EEG)1
Abnormal
Description: Abnormal spectral signature
 Power spectral analysis
 Unreported
Circling1
Increased
Description: Increased circling behavior
 Open field test
 2-3 months
Social interaction: with juveniles1
Decreased
Description: Decreased social interaction
 Reciprocal social interaction test
 2-3 months
Juvenile play1
Decreased
Description: Decreased juvenile play
 Reciprocal social interaction test
 5-6 weeks
Social interaction1
Decreased
Description: Decreased social interaction
 Reciprocal social interaction test
 2-3 months
Social habituation1
Decreased
Description: Decreased social habituation
 Reciprocal social interaction test
 2-3 months
Rearing behavior1
Increased
Description: Increased rearing behavior
 Open field test
 2-3 months
Exploratory activity1
Decreased
Description: Decreased object exploration
 Object preference test
 2-3 months
Reward reinforced choice behavior1
Increased
Description: Increased motivational lever pressing, higher breakpoint
 Operant self-learning paradigm
 2-3 months
Cognitive flexibility: Associative learning: operant self-learning1
Decreased
Description: Decreased associative learning
 Operant self-learning paradigm
 2-3 months
Protein localization: synapse1
Increased
Description: Increase in mGluR1 in striatum
 Fractionation
 Unreported
Targeted expression1
Decreased
Description: Absent protein expression
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative PCR (qRT-PCR)
 Unreported
Targeted expression1
Decreased
Description: Absent protein expression
Exp Paradigm:  Western blot
 Western blot
 Unreported
Protein localization: synapse1
 No Change
 Fractionation
 Unreported
Protein localization: synapse1
 No Change
 Fractionation
 Unreported
Hyperactivity1
 No Change
 Operant self-learning paradigm
 2-3 months
Social approach1
 No Change
 Three-chamber social approach test
 2-3 months
Social memory1
 No Change
 Three-chamber social approach test
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Maternal behavior, Seizure, Sensory

R_SHANK2_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Targeted expression1
Decreased
Description: Decrease in protein expression
Exp Paradigm:  Western blot
 Western blot
 Unreported
Targeted expression1
Decreased
Description: Decrease in protein expression
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative PCR (qRT-PCR)
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
DNM2 dynamin 2 1785 P50570 Y2H; IP/WB; GST
Okamoto PM , et al. 2001
PDE4D phosphodiesterase 4D, cAMP-specific 5144 Q08499 IP/WB; GST
Lee JH , et al. 2007
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
GRID2 glutamate receptor, ionotropic, delta 2 14804 Q61625 Y2H; IP/WB; GST; Surface plasmon resonance (SPR)
Uemura T , et al. 2004
GRIP1 glutamate receptor interacting protein 1 74053 Q925T6 IP/WB
Uemura T , et al. 2004
Khdrbs3 KH domain containing, RNA binding, signal transduction associated 3 13992 Q9R226 RNA-Seq
Traunmller L , et al. 2016
ARHGEF7 Rho guanine nucleotide exchange factor (GEF7) 114559 O55043 Y2H; GST; IP/WB
Park E , et al. 2003
CFTR cystic fibrosis transmembrane conductance regulator homolog 12638 P26361 Y2H; IP/WB
Kim JY , et al. 2003
CTTN cortactin 60465 Q66HL2 Y2H; GST; IP/WB
Du Y , et al. 1998
DBNL Drebrin-like 13169 Q62418 GST; Far Western Blot
Qualmann B , et al. 2004
DLG4 discs, large homolog 4 (Drosophila) 29495 P31016 Y2H; IP/WB
Boeckers TM , et al. 1999
DLGAP1 discs, large (Drosophila) homolog-associated protein 1 65040 P97836 Y2H; GST; IP/WB
Naisbitt S , et al. 1999
DLGAP2 discs, large (Drosophila) homolog-associated protein 2 116681 P97837 Y2H
Boeckers TM , et al. 1999
DLGAP3 discs, large (Drosophila) homolog-associated protein 3 286923 P97838 Y2H
Boeckers TM , et al. 1999
DLGAP4 discs, large homolog-associated protein 4 (Drosophila) 286930 P97839 Y2H
Boeckers TM , et al. 1999
DYNLL1 dynein light chain LC8-type 1 58945 P63170 IP/WB
Naisbitt S , et al. 2000
DYNLL2 dynein light chain LC8-type 2 140734 Q78P75 IP/WB
Naisbitt S , et al. 2000
HOMER1 homer homolog 1 (Drosophila) 29456 Q9Z214 GST; IP/WB
Hwang JI , et al. 2005
ITPR3 inositol 1,4,5-triphosphate receptor, type 3 25679 Q63269 IP/WB
Hwang JI , et al. 2005
LPHN1 latrophilin 1 65096 O88917 Y2H; Far Western Blot; IP/WB
Kreienkamp HJ , et al. 2000
LRRC7 leucine rich repeat containing 7 117284 P70587 IP/WB; GST
Quitsch A , et al. 2005
MYO5A myosin VA 25017 Q9QYF3 IP/WB
Naisbitt S , et al. 2000
PLCB3 phospholipase C, beta 3 29322 Q99JE6 Y2H; GST; IP/WB
Hwang JI , et al. 2005
SLC4A7 solute carrier family 4, sodium bicarbonate cotransporter, member 7 117955 Q9R1N3 Y2H
Kim JY , et al. 2003
SLC9A3 solute carrier family 9 (sodium/hydrogen exchanger), member 3 24784 P26433 Y2H; IP/WB; Surface plasmon resonance (SPR)
Han W , et al. 2005
SSTR2 somatostatin receptor 2 54305 P30680 Y2H; Far Western Blot; IP/WB
Zitzer H , et al. 1999
LZTS2 leucine zipper, putative tumor suppressor 2 495421 Q5U4W1 IP/WB
Gessert S , et al. 2011

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