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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001080420 23 - 7145 NP_001073889 - 1747 only in brain Bonaglia, Durand (2007)

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain forebrain cerebral cortex   highly   brain hindbrain cerebellum   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	developing brain

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed mental retardation other   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