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FLASH GENE
Symbol SHANK3 contributors: mct/npt - updated : 06-12-2015
HGNC name SH3 and multiple ankyrin repeat domains 3
HGNC id 14294
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a SHANK/ProSAP N-terminal (SPN) domain regulates accessibility of the ankyrin repeats through an intramolecular interaction, and is involved in an intramolecular, inhibitory interaction with the ankyrin repeat region (ARR)
  • five ankyrin repeats
  • PDZ domain
  • SH3 domain (proline rich SRC homology 3)
  • C terminal SAM domain (steril alpha motif)
    • HOMOLOGY
    interspecies ortholog to rattus proline rich synapse associated protein
    Homologene
    FAMILY
  • shank family
    • CATEGORY chaperone/stress , structural protein
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic,ribosome
    text
  • near the synapses
  • uncoupling of SHANK3 nuclear shuttling from synaptic activity may represent a molecular mechanism that contributes to the pathology of schizophrenia in patients with mutations in SHANK3
    • basic FUNCTION
  • molecular scaffold in neuronal postsynaptic densities
  • protein of the postsynaptic density (PSD) of excitatory synapses, where it may function as a master scaffolder forming large sheets that may represent the platform for the construction of the PSD complex
  • promotes the formation, maturation, and enlargement of dendritic spines
  • regulate the size and shape of dendritic spines because of their capacity to directly interact with many different PSD components and represent master scaffold proteins of the PSD (Schutt 2009)
  • scaffolding molecule of the postsynaptic density (PSD) of excitatory synapses, which is crucial for PSD assembly and the formation of dendritic spines
  • scaffolding protein that promotes the formation and maturation of dendritic spines (Gauthier 2010)
  • is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements
  • participates in growth cone motility in developing neurons
  • synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses, and plays important roles in the formation, maturation, and maintenance of synapses
  • scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse
  • SHANK3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory
  • act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • SHANK proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the SHANK scaffold
    • protein
  • sharpin
  • binding of SHANK3 C terminus to HOMER1 is critical for its expression at synapses, and HOMER1 stabilizes SHANK3 protein
  • role in regulating metabotropic glutamate receptor 5 (GRM5) expression and signaling at synapses
  • LZTS3 is an interaction partner of the well-known PSD protein SHANK3 and SPAR
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) DEL22Q13 , AUTS20
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    haploinsufficiency of SHANK3 can cause a monogenic form of autism
    Susceptibility
  • to autism spectrum disorder, AUTS20
  • to schizophrenia
    • Variant & Polymorphism other mutation associated with schizophrenia (Gauthier 2010)
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    mental retardationother 
    pharmacological augmentation of GRM5 activity represents a possible new therapeutic approach for patients with SHANK3 mutations
    ANIMAL & CELL MODELS
  • demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice (
  • a mouse genetic model that mimics a human mutation of Shank3 that deletes the Homer-binding domain at the C terminus (&
    • 916;C) and is associated with autism
  • Shank3(+/&
    • 916;C) mice exhibit behavioral phenotypes that parallel symptoms of ASD
  • Shank3 mutant mice exhibit autistic-like behaviors, including impaired social interaction and repetitive behaviors