protein
SH3 and multiple ankyrin repeat domains protein 3
aka Shank3
Gene
SHANK3
Organism
Homo sapiens(9606)
Length
1806 aa
Mass
191,338 Da
SHANK3 (SH3 and multiple ankyrin repeat domains protein 3) is a major postsynaptic density scaffold protein that orchestrates dendritic spine and synapse formation, maturation, and maintenance (UniProt: Q9BYB0). It interconnects glutamate receptors (NMDA-type and metabotropic) with the actin-based cytoskeleton through interactions with adaptor complexes including GKAP/PSD-95 and HOMER, thereby regulating synaptic transmission, plasticity, and growth cone motility.
SHANK3 is expressed in neuronal tissues where it plays critical roles in synapse organization and function. Mutations in SHANK3 are associated with Phelan-McDermid syndrome (PHMDS), a developmental disorder characterized by hypotonia, global developmental delay, severely delayed speech, and autistic behavior (UniProt: Q9BYB0). SHANK3 alterations are also implicated in schizophrenia susceptibility.
SHANK3 is classified as an SFARI Category 1 gene with syndromic autism association (SFARI Cat 1, SFARI Cat syndromic). Its role as a postsynaptic scaffold protein directly linking glutamate receptor signaling to actin dynamics makes it central to the molecular pathology of syndromic autism, particularly in Phelan-McDermid syndrome where SHANK3 haploinsufficiency or loss-of-function mutations are causative.
Generated from the curated entity record below. May contain errors — verify against source links.
Genetic Evidence · ASD
High confidence — strong genetic evidence from multiple studies
Source: SFARI Gene database · gene.sfari.org
Related Publications
Browse all →Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
Ruzzo Elizabeth K et al.Cell2019PMID 31398340Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
Guo Hui et al.Molecular autism2018PMID 30564305Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
C Yuen Ryan K et al.Nature neuroscience2017PMID 28263302Identification of common genetic risk variants for autism spectrum disorder.
Grove Jakob et al.Nature genetics2019PMID 30804558Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis Silvia et al.Nature2014PMID 25363760
Function
Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. 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 through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation
Disease associations
Phelan-McDermid syndromePHMDS
A developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, and minor dysmorphic features.
Schizophrenia 15SCZD15
A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder.
Sources
Last updated 5/6/2026, 5:23:24 AM