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Relevance to Autism

Rare mutations in the SHANK1 gene have been identified in individuals with ASD (Sato et al., 2012).

Molecular Function

Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
SHANK1 Deletions in Males with Autism Spectrum Disorder.
ASD
Negative Association
SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age.
ASD
Support
Excess of rare, inherited truncating mutations in autism.
ASD
Support
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.
ASD, epilepsy/seizures
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Recent Recommendation
Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders
DD, ID
ASD, epilepsy/seizures
Recent Recommendation
Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.
Recent Recommendation
Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.
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
 GEN340R001 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multi-generational 
 GEN340R002 
 copy_number_loss 
  
  
 De novo 
 NA 
 Multiplex 
 GEN340R003 
 missense_variant 
 c.101G>A 
 p.Gly34Asp 
 Familial 
 Paternal 
 Multi-generational 
 GEN340R004 
 missense_variant 
 c.179G>A 
 p.Arg60His 
 Familial 
 Maternal 
 Simplex 
 GEN340R005 
 missense_variant 
 c.877G>A 
 p.Asp293Asn 
 Familial 
 Paternal 
 Multiplex 
 GEN340R006 
 missense_variant 
 c.877G>A 
 p.Asp293Asn 
 Familial 
 Maternal 
 Simplex 
 GEN340R007 
 missense_variant 
 c.1322C>A 
 p.Thr441Asn 
 Familial 
 Paternal 
 Multiplex 
 GEN340R008 
 missense_variant 
 c.1585G>A 
 p.Gly529Arg 
 Familial 
 Paternal 
 Multiplex 
 GEN340R009 
 missense_variant 
 c.2207G>A 
 p.Arg736Gln 
 Familial 
 Paternal 
 Multi-generational 
 GEN340R010 
 missense_variant 
 c.3037C>T 
 p.Pro1013Ser 
 Familial 
 Maternal 
 Multiplex 
 GEN340R011 
 missense_variant 
 c.4361G>A 
 p.Gly1454Glu 
 Familial 
 Paternal 
 Multiplex 
 GEN340R012 
 missense_variant 
 c.4363G>A 
 p.Val1455Met 
 Familial 
 Maternal 
 Simplex 
 GEN340R013 
 missense_variant 
 c.4438G>A 
 p.Ala1480Thr 
 Unknown 
  
 Multiplex 
 GEN340R014 
 missense_variant 
 c.4442C>T 
 p.Ala1481Val 
 Familial 
 Maternal 
 Multiplex 
 GEN340R015 
 missense_variant 
 c.4543G>T 
 p.Gly1515Trp 
 Familial 
 Paternal 
 Multiplex 
 GEN340R016 
 missense_variant 
 c.4799C>T 
 p.Thr1600Ile 
 Familial 
 Paternal 
 Multiplex 
 GEN340R017 
 missense_variant 
 c.4810C>A 
 p.Pro1604Thr 
 Unknown 
 Not maternal 
 Simplex 
 GEN340R018 
 missense_variant 
 c.4855T>A 
 p.Ser1619Thr 
 Familial 
 Paternal 
 Multiplex 
 GEN340R019 
 missense_variant 
 c.4858A>G 
 p.Thr1620Ala 
 Familial 
 Paternal 
 Multiplex 
 GEN340R020 
 missense_variant 
 c.5171T>A 
 p.Leu1724His 
 Familial 
 Maternal 
 Simplex 
 GEN340R021 
 missense_variant 
 c.5776G>A 
 p.Asp1926Asn 
 Familial 
 Maternal 
 Simplex 
 GEN340R022 
 missense_variant 
 c.5779G>A 
 p.Asp1927Asn 
 Unknown 
 Not maternal 
 Simplex 
 GEN340R023 
 missense_variant 
 c.5941C>T 
 p.Arg1981Cys 
 Familial 
 Paternal 
 Simplex 
 GEN340R024 
 missense_variant 
 c.6134G>T 
 p.Gly2045Val 
 Unknown 
 Not maternal 
 Simplex 
 GEN340R025 
 missense_variant 
 c.3947G>A 
 p.Gly1316Asp 
 Familial (1 case), Unknown (1 case) 
 Paternal (1 case) 
 Unknown 
 GEN340R026 
 missense_variant 
 c.5387G>A 
 p.Gly1796Glu 
 Familial (5 cases), Unknown (2 cases) 
 Maternal (4 cases) & paternal (1 case) 
 Unknown 
 GEN340R027 
 missense_variant 
 c.5420C>T 
 p.Pro1807Leu 
 Familial 
 Paternal 
 Multiplex and simplex 
 GEN340R028 
 missense_variant 
 c.16G>A 
 p.Ala6Thr 
 Unknown 
  
 Unknown 
 GEN340R029 
 missense_variant 
 c.1358C>T 
 p.Ala453Val 
 Unknown 
  
 Unknown 
 GEN340R030 
 missense_variant 
 c.1631G>A 
 p.Arg544His 
 Unknown 
  
 Unknown 
 GEN340R031 
 missense_variant 
 c.4391C>T 
 p.Thr1464Met 
 Unknown 
  
 Unknown 
 GEN340R032 
 missense_variant 
 c.4442C>T 
 p.Ala1481Val 
 Unknown 
  
 Unknown 
 GEN340R033 
 missense_variant 
 c.6076G>A 
 p.Gly2026Arg 
 Unknown 
  
 Unknown 
 GEN340R034 
 missense_variant 
 c.5704G>A 
 p.Gly1902Arg 
 De novo 
 NA 
 Simplex 
 GEN340R035 
 splice_site_variant 
 c.2458+1G>A 
  
 De novo 
 NA 
  
 GEN340R036 
 inframe_indel 
 c.3814_3815insGACGGCGGG 
 p.Leu1272delinsArgArgArgVal 
 Unknown 
  
 Unknown 
 GEN340R037 
 frameshift_variant 
 c.3488dup 
 p.Ser1164ValfsTer4 
 De novo 
 NA 
  
 GEN340R038 
 stop_gained 
 c.3355G>T 
 p.Glu1119Ter 
 De novo 
 NA 
  
 GEN340R039 
 frameshift_variant 
 c.3314del 
 p.Gly1105AlafsTer238 
 De novo 
 NA 
  
 GEN340R040 
 stop_gained 
 c.1198C>T 
 p.Arg400Ter 
 De novo 
 NA 
  
 GEN340R041 
 frameshift_variant 
 c.4496_4499del 
 p.Gln1499ProfsTer5 
 De novo 
 NA 
  
 GEN340R042 
 frameshift_variant 
 c.650del 
 p.Leu217Ter 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion
 2
 
19
Duplication
 1
 
19
Deletion-Duplication
 18
 
19
Duplication
 1
 

Model Summary

Shank1 null mice do not demonstrate autism-relevant social interaction deficits, but confirm and extend a role for Shank1 in motor functions.

References

Type
Title
Author, Year
Primary
Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.
Primary
Sociability and motor functions in Shank1 mutant mice.
Additional
Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior.

M_SHANK1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted replacement of exons 14 and 15 encoding the entire PDZ domain was replace with the PGK-neo cassette.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6
Genetic Background: C57BL/6J/129SvJae (B6/Jae)
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_SHANK1_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Targeted replacement of exons 14 and 15 encoding the entire PDZ domain was replace with the PGK-neo cassette.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6
Genetic Background: C57BL/6J/129SvJae (B6/Jae)
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_SHANK1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity1
Decreased
Description: Decreased activity as measured by horizontal activity, total distance traveled, and movement time
Exp Paradigm: Open field test
 Open field test
 3-5 months
Righting response3
Decreased
Description: Decreased righting response indicated by longer time to flip over onto abdomen with four paws touching the surface
Exp Paradigm: Measure of time taken by animal to correct itself after being placed on it's back
 Righting reflex test
 Unreported
General locomotor activity3
Decreased
Description: Decreased locomotor activity indicated by lower distance traveled and lower number of rearing in clean environment
Exp Paradigm: Male mice: open field test in clean environment
 Open field test
 Unreported
Motor coordination and balance1
Decreased
Description: Decreased motor coordination indicated by reduced latency to fall
Exp Paradigm: Accelerating rotarod test
 Accelerating rotarod test
 3-5 months
General locomotor activity3
Decreased
Description: Decreased locomotor activity indicated by lower distance traveled and lower number of rearing after female experience with female urine
Exp Paradigm: Male mice: open field test with female experience through female urine
 Open field test
 Unreported
Motor coordination and balance2
Decreased
Description: Decreased motor coordination and balance demonstrated by shorter latency to fall
Exp Paradigm: Accelerating rotarod test
 Accelerating rotarod test
 7-9 weeks
General locomotor activity2
Decreased
Description: Decreased locomotor activity assayed as center time, horizontal activity, and vertical activity
Exp Paradigm: Open field test
 Open field test
 7-9 weeks
Grip strength2
Decreased
Description: Decreased muscle strength indicated by shorter latency to fall
Exp Paradigm: Inverted wire hang task
 Wire hang test
 Unreported
Post-synaptic density size1
Decreased
Description: Decreased synapse ultrastructure indicated by reduced thickness and length of psd in hippocampal ca1 region
Exp Paradigm: Thin-section electron microscopic micrographs from brains
 Electron microscopy
 Unreported
Dendritic architecture: spine density1
Abnormal
Description: Abnormal synapse morphology indicated by decreased mean spine density and smaller spine size
Exp Paradigm: Quantitative analysis of apical dendritic spines of ca1 pyramidal neurons of hippocampus
 Histology
 Unreported
Synaptic transmission1
Decreased
Description: Decreased basal synaptic transmission indicated by significantly downward shifted input-output curve at high stimulus intensities
Exp Paradigm: Extracellular recordings of ampa receptor-mediated field epsps in the striatum radiatum
 Field potential recordings
 3-5 weeks
Synaptic transmission1
Abnormal
Description: Abnormal ampar mediated mepsc shown by no difference in average mepsc amplitude and decreased frequency of mepsc
Exp Paradigm: Whole-cell patch clamping of brain slices
 Whole-cell patch clamp
 3-5 weeks
Mating behavior3
Decreased
Description: Decreased scent marking indicated by fewer urine traces in proximity to female urine spot and also less time spent in proximity to urine spot
Exp Paradigm: Male mice: scent marking behavior in presence of female urine
 Scent marking test
 Unreported
Ultrasonic vocalization3
Abnormal
Description: Abnormal ultrasonic vocalization calling pattern indicated by failure to change after prior female experience
Exp Paradigm: Male mice: ultrasonic vocalization calling pattern in response to presence of female urine
 Monitoring ultrasonic vocalizations
 Unreported
Ultrasonic vocalization3
Decreased
Description: Decreased ultrasonic vocalizations demonstrated by fewer usv's emitted, reduced calling time, reduced call repitition rate, affected peak frequency of calls, less frequency modulated usvs
Exp Paradigm: Female mice: ultrasonic vocalizations in maternally isolated pups test
 Monitoring ultrasonic vocalizations
 P8
Ultrasonic vocalization3
Abnormal
Description: Abnormal ultrasonic vocalizations indicated by no increase in number of calls across isolation, no increase in time spent vocalizing, no increase in call duration, no increase in call frequency modulation
Exp Paradigm: Female mice: ultrasonic vocalizations in maternally isolated pups test
 Monitoring ultrasonic vocalizations
 P8
Developmental trajectory3
Abnormal
Description: Abnormal developmental trajectory indicated by delayed pinnae detachment and incisor eruption
Exp Paradigm: General observations
 General observations
 Unreported
Size/growth3
Decreased
Description: Decreased body weight in isolated pups
Exp Paradigm: General observations in isolated pups
 General observations
 5 months
Size/growth3
Decreased
Description: Decreased body weight gain
Exp Paradigm: Female mice: general observations
 General observations
 Unreported
Anxiety1
Increased
Description: Increased anxiety demonstrated by fewer transitions between compartments and longerl atency to enter light side
Exp Paradigm: Light/dark test
 Light-dark exploration test
 3-5 months
Anxiety2
Increased
Description: Increased anxiety demonstrated by fewer transitions
Exp Paradigm: Light/dark test
 Light-dark exploration test
 6-7 weeks
Anxiety1
Increased
Description: Increased anxiety demonstrated by less time in center zone
Exp Paradigm: Open field test
 Open field test
 3-5 months
Spatial learning1
Increased
Description: Increased spatial learning demonstrated by a steeper learning curve and better performance level
Exp Paradigm: Eight-arm radial maze task
 Radial maze test
 3-5 months
Cued or contextual fear conditioning1
Decreased
Description: Decreased cued/contextual fear conditioning demonstrated by decreased freezing behavior
Exp Paradigm: Contextual fear conditioning task
 Fear conditioning test
 3-5 months
Spatial reference memory1
Decreased
Description: Decreased long term memory indicated by regression of reference memory performance
Exp Paradigm: Long-term stability of eight-arm radial maze task
 Radial maze test
 3-5 months
Protein expression: in situ protein expression1
Abnormal
Description: Abnormal expression of glutamate receptors, scaffold proteins, and signaling molecules with reduction of gkap, homer1b/c
Exp Paradigm: Protein expression pattern
 Western blot
 Unreported
Protein expression level evidence1
Decreased
Description: Absence of shank1 protein expression in the brain
Exp Paradigm: Shank1 protein expression
 Western blot
 Unreported
Ultrasonic vocalization3
 No change
 Monitoring ultrasonic vocalizations
 Unreported
General characteristics3
 No change
 General observations
 Unreported
General characteristics2
 No change
 General observations
 9-11 weeks
General characteristics1
 No change
 General observations
 Unreported
Mortality/lethality1
 No change
 General observations
 Unreported
Size/growth2
 No change
 General observations
 Unreported
Size/growth3
 No change
 General observations
 Unreported
Anxiety2
 No change
 Elevated plus maze test
 5-6 weeks
Protein expression: in situ protein expression1
 No change
 Western blot
 Unreported
Proteomic profile diversity1
 No change
 Two-dimensional gel electrophoresis (2-dge)
 Unreported
Brain size1
 No change
 Histology
 Unreported
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 3-5 weeks
Synaptic plasticity1
 No change
 Whole-cell patch clamp
 3-5, 7-9 weeks
Core body temperature3
 No change
 General observations
 Unreported
Hearing2
 No change
 Preyer's reflex test
 Unreported
Olfaction2
 No change
 Olfactory habituation-dishabituation test
 12-14 weeks
Pain or nociception2
 No change
 Tail flick test
 Unreported
Pain or nociception2
 No change
 Hot plate test
 Unreported
Sensorimotor gating2
 No change
 Prepulse inhibition
 Unreported
Startle response: acoustic stimulus2
 No change
 Acoustic startle reflex test
 Unreported
Vision2
 No change
 Forepaw reaching test
 Unreported
Huddling behavior2
 No change
 General observations
 Unreported
Mating behavior3
 No change
 Scent marking test
 Unreported
Nest building behavior2
 No change
 General observations
 Unreported
Self grooming: social context2
 No change
 General observations
 10-12 weeks
Social approach2
 No change
 Three-chamber social approach test
 8-10 weeks
Social interaction2
 No change
 Reciprocal social interaction test
 3 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_SHANK1_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Developmental trajectory2
Abnormal
Description: Abnormal developmental trajectory indicated by delayed pinnae detachment and incisor eruption
Exp Paradigm: General observations
 General observations
 Unreported
General characteristics2
 No change
 General observations
 Unreported
General characteristics1
 No change
 General observations
 9-11 weeks
Size/growth1
 No change
 General observations
 Unreported
Anxiety2
 No change
 Elevated plus maze test
 5-6 weeks
Anxiety1
 No change
 Light-dark exploration test
 6-7 weeks
General locomotor activity1
 No change
 Open field test
 7-9 weeks
General locomotor activity2
 No change
 Open field test
 Unreported
General locomotor activity2
 No change
 Open field test
 Unreported
Grip strength1
 No change
 Wire hang test
 Unreported
Motor coordination and balance1
 No change
 Accelerating rotarod test
 7-9 weeks
Righting response2
 No change
 Righting reflex test
 Unreported
Core body temperature1
 No change
 Body temperature measurement
 Unreported
Hearing1
 No change
 Preyer's reflex test
 Unreported
Olfaction1
 No change
 Olfactory habituation-dishabituation test
 12-14 weeks
Pain or nociception1
 No change
 Tail flick test
 Unreported
Pain or nociception1
 No change
 Hot plate test
 Unreported
Sensorimotor gating1
 No change
 Prepulse inhibition
 Unreported
Startle response: acoustic stimulus1
 No change
 Acoustic startle reflex test
 Unreported
Vision1
 No change
 Forepaw reaching test
 Unreported
Self grooming: social context1
 No change
 General observations
 10-12 weeks
Social approach1
 No change
 Three-chamber social approach test
 8-10 weeks
Social interaction1
 No change
 Reciprocal social interaction test
 3 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ARHGEF7 Rho guanine nucleotide exchange factor (GEF7) 54126 Q9ES28 Y2H; GST; IP/WB
Park E , et al. 2003
BAI2 brain-specific angiogenesis inhibitor 2 576 O60241 Y2H
Kreienkamp HJ , et al. 2000
BAIAP2 BAI1-associated protein 2 10458 Q9UQB8 Y2H; Overlay binding assay; IP/WB
Soltau M , et al. 2002
DNM2 dynamin 2 1785 P50570 Y2H; IP/WB; Far Western Blot
Okamoto PM , et al. 2001
LPHN1 latrophilin 1 22859 O94910 Far Western Blot
Kreienkamp HJ , et al. 2000
LPHN2 latrophilin 2 23266 O95490 Y2H
Kreienkamp HJ , et al. 2000
SHANK1 SH3 and multiple ankyrin repeat domains 1 50944 Q9Y566 GST; IP/WB
Romorini S , et al. 2004
SHANK3 SH3 and multiple ankyrin repeat domains 3 85358 Q9BYB0 Y2H; IP/WB
Sakai Y , et al. 2011
SPTAN1 spectrin, alpha, non-erythrocytic 1 64159 P16086 Affinity chromatography; MS; IP/WB; GST
Bckers TM , et al. 2001
SSTR2 somatostatin receptor 2 54305 P30680 Y2H; GST; IP/WB
Zitzer H , et al. 1999
STAT1 signal transducer and activator of transcription 1, 91kDa 6772 P42224 Y2H
Bandyopadhyay S , et al. 2010
TSC1 tuberous sclerosis 1 7248 Q92574 Y2H; IP/WB
Sakai Y , et al. 2011
FMR1 fragile X mental retardation 1 14265 P35922 IP; qRT-PCR
Schtt J , et al. 2009
MET met proto-oncogene 17295 P16056 IP; LC-MS/MS
Xie Z , et al. 2016
DLGAP1 discs, large (Drosophila) homolog-associated protein 1 9229 O14490 X-ray crystallography
Im YJ , et al. 2003
DNM1 dynamin 1 1759 Q05193 IP/WB
Okamoto PM , et al. 2001
HOMER1 homer homolog 1 (Drosophila) 9456 Q86YM7 Y2H; GST; IP/WB
Tu JC , et al. 1999
Homer1 homer homolog 1 (Drosophila) 29456 Q9Z214 Y2H; GST; IP/WB
Tu JC , et al. 1999
SHARPIN SHANK-associated RH domain interactor 81859 Q9EQL9 Y2H; IP/WB
Lim S , et al. 2001
lzts2 leucine zipper, putative tumor suppressor 2 495421 Q5U4W1 IP/WB
Gessert S , et al. 2011

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