SHANK3 SH3 and multiple ankyrin repeat domains 3 [Homo sapiens] - Gene

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Summary

Official Symbol: SHANK3provided by HGNC
Official Full Name: SH3 and multiple ankyrin repeat domains 3provided by HGNC
Primary source: HGNC:14294
See related: Ensembl:ENSG00000251322; MIM:606230
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PSAP2; SCZD15; PROSAP2; SPANK-2; DEL22q13.3; KIAA1650
Summary: This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

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Genomic context

Location :: 22q13.3

Sequence :: Chromosome: 22; NC_000022.10 (51113070..51171641)

See SHANK3 in Epigenomics, MapViewer

Chromosome 22 - NC_000022.10 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

the data of this study provided new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies.
Title: SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.
SHANK3 microdeletion is an important genetic component for autism, which may explain 2% typical autism cases.
Title: [Copy-number variations of SHANK3 and related clinical phenotypes in children with autism].
The SHANK3 gene was analyzed in 128 autistic patients with manifestations similar to those seen in the 22q13.3 deletion syndrome.
Title: Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.
Deletion size in the SHANK3 gene and adjacent regions determine the severity of phenotypes in Phelan-McDermid syndrome (22q13 deletion syndrome).
Title: Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).
[review] The presumptive exon containing the variant in the neurodevelopmentally disabled autism case highlighted in this review is not likely to be present in most or all SHANK3 transcripts.
Title: Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.
A translocation between Xq21.33 and 22q13.33 causes an intragenic SHANK3 deletion in a woman with Phelan-McDermid syndrome and hypergonadotropic hypogonadism.
Title: A translocation between Xq21.33 and 22q13.33 causes an intragenic SHANK3 deletion in a woman with Phelan-McDermid syndrome and hypergonadotropic hypogonadism.
Observational study and meta-analysis of gene-disease association. (HuGE Navigator)
Title: Linkage and candidate gene studies of autism spectrum disorders in European populations.
De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.
Title: De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.
SHANK3 deletions may be limited to lower functioning individuals with autism
Title: Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.
Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3 is reported.
Title: Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.

Submit: New GeneRIF Correction See all (18)

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Phenotypes

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Autism, chromosome 22q13.3 deletion syndrome-related

MIM: 606230

Phelan-McDermid syndrome (22q13.3 deletion syndrome) is characterized by neonatal hypotonia, global developmental delay, absent to severely delayed speech, and normal to accelerated growth. Most individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autistic-like affect.

Diagnosis Testing

Clinical diagnostic criteria for Phelan-McDermid syndrome have not been established. Phelan-McDermid syndrome results from terminal or interstitial deletion of chromosome 22q13.3. On rare occasion an apparently balanced chromosome rearrangement or a mutation disrupts SHANK3. Prior to about 2006, deletion of 22q13.3 was commonly diagnosed by high resolution chromosome analysis and fluorescence in situ hybridization (FISH); since 2006, chromosome microarray analysis (CMA), a more sensitive and accurate method for detecting this deletion, is preferred.

Genetic Counseling

Phelan-McDermid syndrome results from a de novo or inherited chromosome abnormality, which can be determined by parental chromosome analysis. Prenatal testing for 22q13.3 deletion is possible for pregnancies at increased risk.

References

PMID: 20301377

Schizophrenia 15

MIM: 613950

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Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
Q9BYB0	Q8WXI2	CNKSR2	HPRD	PubMed
Q9BYB0	P26367	PAX6	HPRD	PubMed
BioGRID:124487	BioGRID:114393	ARHGEF7	BioGRID	PubMed	Affinity Capture-Western; Two-hybrid
BioGRID:124487	BioGRID:114660	DLGAP1	BioGRID	PubMed	Two-hybrid
BioGRID:124487	BioGRID:114659	DLGAP2	BioGRID	PubMed	Two-hybrid
BioGRID:124487	BioGRID:121839	DLGAP3	BioGRID	PubMed	Two-hybrid
BioGRID:124487	BioGRID:116513	DLGAP4	BioGRID	PubMed	Two-hybrid
BioGRID:124487	BioGRID:112587	SPTAN1	BioGRID	PubMed	Two-hybrid

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General gene information

Markers

D22S1726 (e-PCR)
- UniSTS:71686

NoName (e-PCR)
- UniSTS:146590

Genotypes

Homology

Homologs of the SHANK3 gene: The SHANK3 gene is conserved in chimpanzee, dog, cow, mouse, rat, zebrafish, and C.elegans.
Map Viewer (Mouse, Rat)

Pathways from BioSystems

Glutamatergic synapse, organism-specific biosystem (from KEGG)
Glutamatergic synapse, organism-specific biosystemGlutamate is the major excitatory neurotransmitter in the mammalian central nervous system(CNS). Glutamate is packaged into synaptic vesicles in the presynaptic terminal. Once released into the synap...
Glutamatergic synapse, conserved biosystem (from KEGG)
Glutamatergic synapse, conserved biosystemGlutamate is the major excitatory neurotransmitter in the mammalian central nervous system(CNS). Glutamate is packaged into synaptic vesicles in the presynaptic terminal. Once released into the synap...
Signaling events regulated by Ret tyrosine kinase, organism-specific biosystem (from Pathway Interaction Database)
Signaling events regulated by Ret tyrosine kinase, organism-specific biosystem
Signaling events regulated by Ret tyrosine kinase

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
GKAP/Homer scaffold activity	ISS Inferred from Sequence or Structural Similarity more info
SH3 domain binding	IEA Inferred from Electronic Annotation more info
ionotropic glutamate receptor binding	ISS Inferred from Sequence or Structural Similarity more info
protein C-terminus binding	ISS Inferred from Sequence or Structural Similarity more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
scaffold protein binding	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
brain morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
dendritic spine morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
locomotory exploration behavior	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of cell volume	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor activity	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of excitatory postsynaptic membrane potential	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of long-term neuronal synaptic plasticity	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of synapse structural plasticity	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of synaptic transmission, glutamatergic	ISS Inferred from Sequence or Structural Similarity more info
postsynaptic density assembly	ISS Inferred from Sequence or Structural Similarity more info
regulation of behavioral fear response	ISS Inferred from Sequence or Structural Similarity more info
social behavior	ISS Inferred from Sequence or Structural Similarity more info
striatal medium spiny neuron differentiation	ISS Inferred from Sequence or Structural Similarity more info
vocalization behavior	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
cell junction	IEA Inferred from Electronic Annotation more info
cytoplasm	IEA Inferred from Electronic Annotation more info
neuron spine	ISS Inferred from Sequence or Structural Similarity more info
plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
postsynaptic density	ISS Inferred from Sequence or Structural Similarity more info
postsynaptic membrane	IEA Inferred from Electronic Annotation more info
synapse	IEA Inferred from Electronic Annotation more info

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General protein information

Preferred Names: SH3 and multiple ankyrin repeat domains protein 3

Names: SH3 and multiple ankyrin repeat domains protein 3; shank postsynaptic density protein; proline rich synapse associated protein 2

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_008607.2 RefSeqGene

Range

5001..63858

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_033517.1 → NP_277052.1 SH3 and multiple ankyrin repeat domains protein 3

Status: REVIEWED

Source sequence(s)

AB051437, AB569469, BC018856

UniProtKB/TrEMBL

D7UT47

Conserved Domains (6) summary

cd00992
Location:570 – 662
Blast Score: 112

PDZ_signaling; PDZ domain found in a variety of Eumetazoan signaling molecules, often in tandem arrangements. May be responsible for specific protein-protein interactions, as most PDZ domains bind C-terminal polypeptides, and binding to internal (non-C-terminal) ...

cd00174
Location:475 – 527
Blast Score: 138

SH3; Src homology 3 domains; SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of ...

cd00204
Location:210 – 335
Blast Score: 270

ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...

cd09506
Location:1664 – 1729
Blast Score: 334

SAM_Shank1,2,3; SAM domain of Shank1,2,3 family proteins

pfam07647
Location:1668 – 1728
Blast Score: 154

SAM_2; SAM domain (Sterile alpha motif)

pfam12796
Location:222 – 313
Blast Score: 167

Ank_2; Ankyrin repeats (3 copies)

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000022.10 Reference GRCh37.p5 Primary Assembly

Range

51113070..51171641

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000154.1 Alternate HuRef

Range

34005374..34064053

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NM_001080420.1: Suppressed sequence

Description

NM_001080420.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC000036.5 (8226..35462)	None
genomic	AC000050.22 (10604..42166)	None
genomic	AC002056.1 (7539..10031)	None
genomic	DQ173561.1	ABA00478.2
genomic	HQ848666.1	ADY38945.1
genomic	HQ848667.1	ADY38946.1
mRNA	AB051437.1	BAB33320.1
mRNA	AB569469.1	BAJ09793.1
mRNA	AK074038.1	BAB84864.1
mRNA	BC018856.2	None
mRNA	BC045765.1	None
mRNA	BC062987.1	AAH62987.1

Protein Accession	Links
Protein Accession	GenPept Link	UniProtKB Link
Q3S3B4	GenPept	UniProtKB/TrEMBL:Q3S3B4
Q6P5A2	GenPept	UniProtKB/TrEMBL:Q6P5A2
Q9BYB0.2	GenPept	UniProtKB/Swiss-Prot:Q9BYB0