Human Gene Module / Chromosome 1 / DLGAP3

DLGAP3DLG associated protein 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
10 / 5
Aliases
DLGAP3, DAP3,  SAPAP3
Associated Syndromes
-
Chromosome Band
1p34.3
Associated Disorders
-
Relevance to Autism

Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD) , Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011).

Molecular Function

May play a role in the molecular organization of synapses and neuronal cell signaling. Could be an adapter protein linking ion channel to the subsynaptic cytoskeleton. May induce enrichment of PSD-95/SAP90 at the plasma membrane.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DLGAP3 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family Boeckers TM , et al. (1999) No -
2 Primary Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice Welch JM , et al. (2007) No -
3 Positive Association Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study Bienvenu OJ , et al. (2008) No -
4 Support Multiple rare SAPAP3 missense variants in trichotillomania and OCD Zchner S , et al. (2008) No -
5 Support Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics Bennett EJ , et al. (2010) No -
6 Positive Association Family-based genetic association study of DLGAP3 in Tourette Syndrome Crane J , et al. (2010) No -
7 Support Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population Boardman L , et al. (2011) No -
8 Recent Recommendation Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder Wan Y , et al. (2013) No -
9 Recent Recommendation Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice Xu P , et al. (2013) No -
10 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.33T>A p.His11Gln missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.566C>T p.Ala189Val missense_variant Unknown - Simplex 19096451 Zchner S , et al. (2008)
c.1267C>T p.Arg423Cys missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.22C>T p.Arg8Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.38G>A p.Arg13His missense_variant Unknown - Multi-generational 19096451 Zchner S , et al. (2008)
c.566C>T p.Ala189Val missense_variant Unknown - Multi-generational 19096451 Zchner S , et al. (2008)
c.2728A>G p.Lys910Glu missense_variant Familial Paternal Multiplex 19096451 Zchner S , et al. (2008)
c.1568C>A p.Thr523Asn missense_variant Unknown - Multi-generational 19096451 Zchner S , et al. (2008)
c.1816C>A p.Pro606Thr missense_variant Unknown - Simplex for OCD; multi-generational for NDDs/NPDs 19096451 Zchner S , et al. (2008)
c.442_443insGGCCAGCAGGGGCAG p.Gly147_Ala148insGlyProAlaGlyAla inframe_insertion Unknown - Multiplex 19096451 Zchner S , et al. (2008)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- A/G downstream_gene_variant - - - 19051237 Bienvenu OJ , et al. (2008)
c.2001-7405C>T A/G intron_variant - - - 21184590 Crane J , et al. (2010)
c.-134-5896A>C T/G intron_variant - - - 19051237 Bienvenu OJ , et al. (2008)
c.1108-1416C>A T/G intron_variant - - - 19051237 Bienvenu OJ , et al. (2008)
c.1386+5192T>A;c.1386+5192T>C A/G intron_variant - - - 19051237 Bienvenu OJ , et al. (2008)
SFARI Gene score
2

Strong Candidate

The protein encoded by the DLGAP3 gene interacts with the proteins encoded by the high confidence ASD genes SHANK2, SHANK3, and CUL3 (Boeckers et al., 1999; Bennett et al., 2010). Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011; Boardman et al., 2011).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

The protein encoded by the DLGAP3 gene interacts with the proteins encoded by the high confidence ASD genes SHANK2, SHANK3, and CUL3 (Boeckers et al., 1999; Bennett et al., 2010). Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011; Boardman et al., 2011).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

The protein encoded by the DLGAP3 gene interacts with the proteins encoded by the high confidence ASD genes SHANK2, SHANK3, and CUL3 (Boeckers et al., 1999; Bennett et al., 2010). Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011; Boardman et al., 2011).

Reports Added
[New Scoring Scheme]
4/1/2019
4
icon
4

Decreased from 4 to 4

Description

The protein encoded by the DLGAP3 gene interacts with the proteins encoded by the high confidence ASD genes SHANK2, SHANK3, and CUL3 (Boeckers et al., 1999; Bennett et al., 2010). Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011; Boardman et al., 2011).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2018
icon
4

Increased from to 4

Description

The protein encoded by the DLGAP3 gene interacts with the proteins encoded by the high confidence ASD genes SHANK2, SHANK3, and CUL3 (Boeckers et al., 1999; Bennett et al., 2010). Deletion of DLGAP3 in mice results in increased anxiety and compulsive grooming behavior, which can be alleviated by a selective serotonin reuptake inhibitor, as well as defects in cortico-striatal synapses (Welch et al., 2007). Rare and common variants in the DLGAP3 have subsequently been shown to associate with obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and pathological grooming behaviors in humans (Bienvenu et al., 2008; Zuchner et al., 2009; Crane et al., 2011; Boardman et al., 2011).

Reports Added
[Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.2010]
Krishnan Probability Score

Score 0.49169454732233

Ranking 5220/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99963851581356

Ranking 874/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94417840463202

Ranking 15974/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.38120201794075

Ranking 1671/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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