SHANK3 Gene: Structure, Function, and Clinical Significance
A master scaffold protein of the postsynaptic density, implicated in neurodevelopmental and neuropsychiatric disorders.
Gene Information Card
| Symbol | SHANK3 |
|---|---|
| Full Name | SH3 and multiple ankyrin repeat domains 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 22q13.33 |
| NCBI Gene ID | 85358 ncbi.nlm.nih.gov/gene/85358 |
| Ensembl ID | ENSG00000251322 |
| UniProt ID | Q9BYB0 |
| OMIM ID | 606230 |
| HGNC ID | 14524 |
| Aliases | PSD-95-binding protein; ProSAP2; SPANK-2; KIAA1650 |
Description
The SHANK3 gene encodes a master scaffold protein localized at the postsynaptic density of excitatory synapses. It organizes glutamate receptor complexes, cytoskeletal elements, and signaling molecules, playing a critical role in synaptic development and plasticity. Mutations and deletions of SHANK3 are strongly associated with neurodevelopmental disorders, particularly Phelan-McDermid syndrome and autism spectrum disorder.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Phelan-McDermid syndrome | Haploinsufficiency due to 22q13.3 deletion or SHANK3 mutation leads to reduced scaffold function, impairing synaptic signaling. | ClinVar, OMIM |
| Autism spectrum disorder | Loss-of-function mutations disrupt synaptic protein complexes, altering neuronal connectivity. | ClinVar, OMIM |
| Intellectual disability | Pathogenic variants impair synaptic plasticity, affecting cognitive function. | ClinVar |
| Schizophrenia | Rare variants contribute to synaptic dysfunction in glutamatergic pathways. | ClinVar, OMIM |
| Bipolar disorder | Association studies suggest SHANK3 variants increase susceptibility. | ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | High | High |
| Testis | Low | Low |
| Heart | Low | Low |
| Liver | Not detected | Not detected |
| Kidney | Not detected | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | High | Neuronal-like expression |
| U-87 MG (glioblastoma) | Medium | Glial expression |
| HeLa (cervical carcinoma) | Low | Non-neuronal expression |
| HEK293 (embryonic kidney) | Low | Ectopic expression used in studies |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.3679C>T (p.Arg1231Ter) | Nonsense | Rare | Loss of function, truncation |
| c.2268+1G>A | Splice site | Rare | Aberrant splicing, loss of function |
| c.2590_2591del (p.Val864LeufsTer2) | Frameshift | Rare | Loss of function, premature termination |
| c.1321C>T (p.Arg441Ter) | Nonsense | Rare | Loss of function, truncation |
| c.3679C>T (p.Arg1231Ter) | Nonsense | Rare | Loss of function, truncation |
Mutation functional classification
Loss of Function (LOF)
Most SHANK3 mutations are loss-of-function, leading to haploinsufficiency or dominant-negative effects, reducing scaffold protein levels and disrupting synaptic organization.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well characterized; some missense variants may alter protein interactions but are not clearly activating.
Dominant Negative (DN)
Truncating mutations can produce dominant-negative fragments that interfere with wild-type SHANK3 function, especially in the postsynaptic density.
View complete mutation data：
Gene Ontology (GO)
| • GO:0005200 (structural constituent of cytoskeleton) | • GO:0005515 (protein binding) |
| • GO:0005737 (cytoplasm) | • GO:0014069 (postsynaptic density) |
| • GO:0045202 (synapse) | • GO:0030054 (cell junction) |
| • GO:0005886 (plasma membrane) | • GO:0005856 (cytoskeleton) |
| • GO:0007268 (chemical synaptic transmission) | • GO:0050804 (modulation of chemical synaptic transmission) |
Pathways
• Glutamatergic synapse
• Postsynaptic density organization
• Synaptic signaling
• Neuroactive ligand-receptor interaction
• Long-term potentiation
Protein Summary
SHANK3 is a large scaffold protein (approximately 180 kDa) that contains multiple ankyrin repeats, an SH3 domain, a PDZ domain, a proline-rich region, and a SAM domain. It interacts with numerous postsynaptic proteins, including NMDA and AMPA receptor complexes, Homer, and cortactin, to organize the postsynaptic density. Its expression is crucial for synaptic maturation and plasticity, and its dysfunction underlies several neuropsychiatric conditions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SHANK3 Knockout HEK293 Cell Line | EDJ-KQ2753 | Human | 85358 | Details Get a Quote |
| SHANK3 Knockout A-549 Cell Line | EDJ-KQ25033 | Human | 85358 | Details Get a Quote |
| SHANK3 Knockout HCT 116 Cell Line | EDJ-KQ25034 | Human | 85358 | Details Get a Quote |
| SHANK3 Knockout HeLa Cell Line | EDJ-KQ25035 | Human | 85358 | Details Get a Quote |
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