Human Gene Module / Chromosome 7 / CTTNBP2

CTTNBP2cortactin binding protein 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 15
Rare Variants / Common Variants
43 / 0
EAGLE Score
24.8
Strong Learn More
Aliases
CTTNBP2, Orf4,  C7orf8,  CORTBP2,  FLJ34229,  KIAA1758,  MGC104579
Associated Syndromes
-
Chromosome Band
7q31.31
Associated Disorders
ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Rare mutations in the CTTNBP2 gene were originally reported in individuals with autism in Cheung et al., 2001; however, genetic association was not found in this report when allele frequencies were compared to the control cohort. A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Functional analysis of ASD-associated CTTNBP2 variants (originally reported in De Rubeis et al., 2014) in Shih et al., 2020 found that four ASD-associated variants resulted in reduced dendritic spine density in cultured hippocampal neurons; furthermore, mice that were heterozygous for the ASD-associated p.Met121Ile variant (p.Met120Ile in mouse) exhibited reduced dendritic spine density and reduced social interactions. Shih et al., 2022 reported that liquid-liquid phase separation and zinc-induced liquid-to-gel phase transition regulated the synaptic distribution and protein-protein interaction of CTTNBP2, which formed self-assembled condensates throught its C-terminal intrinsically disordered region and facilitated SHANK3 co-condensation at dendritic spines, while zinc was found to bind to CTTNBP2, promoting higher-order assemblies and leading to reduced mobility and enhanced stability and synaptic retention of CTTNBP2 condensates; ASD-linked mutations were subsequently found to alter condensate formation and synaptic retention of CTTNBP2 and impaired mouse social behaviors, which could be ameliorated by zinc supplementation.

Molecular Function

A similar gene in rat interacts with a central regulator of the actin cytoskeleton.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CTTNBP2 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Identification of the human cortactin-binding protein-2 gene from the autism candidate region at 7q31 Cheung J , et al. (2001) Yes -
2 Highly Cited Transcription-dependent spatial arrangements of CFTR and adjacent genes in human cell nuclei Zink D , et al. (2004) No -
3 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
4 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Epilepsy, ASD
5 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
6 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
9 Support CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors Shih PY et al. (2020) Yes -
10 Recent Recommendation Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms Shih PY et al. (2020) Yes -
11 Support - Woodbury-Smith M et al. (2022) Yes -
12 Recent Recommendation - Shih PY et al. (2022) Yes -
13 Support - Zhou X et al. (2022) Yes -
14 Support - Yen TL et al. (2022) Yes -
15 Support - Xie Y et al. (2022) Yes -
Rare Variants   (43)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>T p.(=) synonymous_variant - - - 11707066 Cheung J , et al. (2001)
c.3729T>G p.Leu1213Val missense_variant - - - 11707066 Cheung J , et al. (2001)
c.3402C>A p.Asp1134Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4403G>T p.Arg1468Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.344T>C p.Met115Thr missense_variant De novo - Simplex 36670631 Xie Y et al. (2022)
c.1444C>A p.Leu482Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1252C>T p.Gln418Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2752C>T p.His918Tyr missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.3360T>G p.Tyr1120Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2445C>G p.Tyr815Ter stop_gained Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2461G>T p.Gly821Ter stop_gained Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.3970C>T p.Arg1324Cys missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3970C>T p.Arg1324Cys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.124C>T p.Arg42Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4688G>T p.Gly1563Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2758G>T p.Ala920Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3113A>G p.Asn1038Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3989C>T p.Ala1330Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4929C>G p.Asn1643Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4262-2A>G - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1606C>T p.Arg536Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4365G>A p.Trp1455Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.124C>T p.Arg42Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2652_2653del p.Phe884LeufsTer10 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.3473_3476del p.Val1158GlufsTer4 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.337G>A p.Ala113Thr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.363G>A p.Met121Ile missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1027G>A p.Gly343Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2087C>A p.Thr696Asn missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2575C>T p.Leu859Phe missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2843G>A p.Arg948Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2651_2652del p.Phe884Ter frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3293G>T p.Ser1098Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3332A>T p.Gln1111Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3940G>A p.Val1314Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3947dup p.Gln1317SerfsTer3 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4457del p.Asn1486IlefsTer7 frameshift_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.4815dup p.Val1606CysfsTer5 frameshift_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2279_2280del p.Val760GlufsTer14 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.3423_3424dup p.Leu1142HisfsTer4 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4500_4501del p.Ser1501LysfsTer8 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4500_4501del p.Ser1501LysfsTer8 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.4975_4976dup p.Pro1661AsnfsTer31 frameshift_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

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.

10/1/2020
2
icon
2

Score remained at 2

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

Reports Added
[Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms2020]
4/1/2020
2
icon
2

Score remained at 2

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

Reports Added
[CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). In a linkage region, but no evidence for association with autism (PMID: 11707066).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
10/1/2014
5
icon
3

Decreased from 5 to 3

Description

A de novo LoF variant in the CTTNBP2 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CTTNBP2 as a gene meeting high statistical significance with a 0.01

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

In a linkage region, but no evidence for association with autism (PMID: 11707066).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

In a linkage region, but no evidence for association with autism (PMID: 11707066).

Krishnan Probability Score

Score 0.49482584782543

Ranking 3398/25841 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 2.5991587968103E-6

Ranking 14710/18225 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 0.062956824558099

Ranking 51/18665 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
Larsen Cumulative Evidence Score

Score 40

Ranking 47/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.4982407927647

Ranking 536/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CCT3 chaperonin containing TCP1, subunit 3 (gamma) Human Protein Binding 7203 P49368
CCT5 chaperonin containing TCP1, subunit 5 (epsilon) Human Protein Binding 22948 P48643
CCT8 chaperonin containing TCP1, subunit 8 (theta) Human Protein Binding 10694 P50990
FAM40B striatin interacting protein 2 Human Protein Binding 57464 Q9ULQ0
MST4 Serine/threonine-protein kinase MST4 Human Protein Binding 51765 Q9P289
PDCD10 programmed cell death 10 Human Protein Binding 11235 Q9BUL8
PRDM14 PR domain zinc finger protein 14 Human Protein Binding 63978 Q9GZV8
STK24 serine/threonine kinase 24 Human Protein Binding 8428 Q9Y6E0
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