Human Gene Module / Chromosome 17 / YWHAE

YWHAEtyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
2 / 0
Aliases
YWHAE, 14-3-3E,  KCIP-1,  MDCR,  MDS
Associated Syndromes
-
Chromosome Band
17p13.3
Associated Disorders
-
Relevance to Autism

A novel recurrent duplication involving the YWHAE gene was identified in Prasad et al., 2012 in two unrelated ASD cases but not in 5,139 controls (FET two-tailed p=0.01421). Bruno et al., 2010 found that the minimal region of overlap for cases with 17p13.3 microduplication, which includes autism as a phenotype, spans 72 kb and encompasses a single gene, YWHAE. Curry et al., 2013 described 34 additional patients with 17p13.3 duplications from 21 families and found that ASD was observed in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes.

Molecular Function

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the mouse ortholog. It interacts with CDC25 phosphatases, RAF1 and IRS1 proteins, suggesting its role in diverse biochemical activities related to signal transduction, such as cell division and regulation of insulin sensitivity.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to YWHAE (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes Bruno DL , et al. (2010) No -
2 Support Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems Capra V , et al. (2012) Yes -
3 Primary A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
4 Support The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes Curry CJ , et al. (2013) No -
5 Support - Cornell B , et al. (2016) No -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal Multi-generational 23035971 Capra V , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A novel recurrent duplication involving the YWHAE gene was identified in Prasad et al., 2012 in two unrelated ASD cases but not in 5,139 controls (FET two-tailed p=0.01421). Bruno et al., 2010 found that the minimal region of overlap for cases with 17p13.3 microduplication, which includes autism as a phenotype, spans 72 kb and encompasses a single gene, YWHAE. Curry et al., 2013 described 34 additional patients with 17p13.3 duplications from 21 families and found that ASD was observed in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes. Cornell et al., 2016 discovered that 14-3-3, the protein encoded by the YWHAE gene, interacted with the microtubule binding protein doublecortin (encoded by the DCX gene), thereby preventing its degradation; the authors also found that 14-3-3 overexpression disrupted neurite formation, whereas 14-3-3 deficiency in flox mice resulted in an increase in neurite formation.

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

A novel recurrent duplication involving the YWHAE gene was identified in Prasad et al., 2012 in two unrelated ASD cases but not in 5,139 controls (FET two-tailed p=0.01421). Bruno et al., 2010 found that the minimal region of overlap for cases with 17p13.3 microduplication, which includes autism as a phenotype, spans 72 kb and encompasses a single gene, YWHAE. Curry et al., 2013 described 34 additional patients with 17p13.3 duplications from 21 families and found that ASD was observed in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes. Cornell et al., 2016 discovered that 14-3-3, the protein encoded by the YWHAE gene, interacted with the microtubule binding protein doublecortin (encoded by the DCX gene), thereby preventing its degradation; the authors also found that 14-3-3 overexpression disrupted neurite formation, whereas 14-3-3 deficiency in flox mice resulted in an increase in neurite formation.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A novel recurrent duplication involving the YWHAE gene was identified in Prasad et al., 2012 in two unrelated ASD cases but not in 5,139 controls (FET two-tailed p=0.01421). Bruno et al., 2010 found that the minimal region of overlap for cases with 17p13.3 microduplication, which includes autism as a phenotype, spans 72 kb and encompasses a single gene, YWHAE. Curry et al., 2013 described 34 additional patients with 17p13.3 duplications from 21 families and found that ASD was observed in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes. Cornell et al., 2016 discovered that 14-3-3, the protein encoded by the YWHAE gene, interacted with the microtubule binding protein doublecortin (encoded by the DCX gene), thereby preventing its degradation; the authors also found that 14-3-3 overexpression disrupted neurite formation, whereas 14-3-3 deficiency in flox mice resulted in an increase in neurite formation.

Reports Added
[New Scoring Scheme]
7/1/2016
icon
4

Increased from to 4

Description

A novel recurrent duplication involving the YWHAE gene was identified in Prasad et al., 2012 in two unrelated ASD cases but not in 5,139 controls (FET two-tailed p=0.01421). Bruno et al., 2010 found that the minimal region of overlap for cases with 17p13.3 microduplication, which includes autism as a phenotype, spans 72 kb and encompasses a single gene, YWHAE. Curry et al., 2013 described 34 additional patients with 17p13.3 duplications from 21 families and found that ASD was observed in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes. Cornell et al., 2016 discovered that 14-3-3?, the protein encoded by the YWHAE gene, interacted with the microtubule binding protein doublecortin (encoded by the DCX gene), thereby preventing its degradation; the authors also found that 14-3-3? overexpression disrupted neurite formation, whereas 14-3-3? deficiency in flox mice resulted in an increase in neurite formation.

Reports Added
[The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.2013] [Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.2012] [Regulation of neuronal morphogenesis by 14-3-3epsilon (Ywhae) via the microtubule binding protein, doublecortin.2016]
Krishnan Probability Score

Score 0.57154399438037

Ranking 772/25841 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 0.9641611419606

Ranking 2464/18225 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 0.91422071618383

Ranking 8131/18665 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 4

Ranking 327/461 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 0.19181190283657

Ranking 4398/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CGN Cingulin Human Protein Binding 57530 Q9P2M7
FAM163A Protein FAM163A Human Protein Binding 148753 Q96GL9
FAM189A2 Protein FAM189A2 Human Protein Binding 9413 Q15884
KIAA0748 Protein TESPA1 Human Protein Binding 9840 A2RU30-2
SMTNL2 Smoothelin-like protein 2 Human Protein Binding 342527 Q2TAL5-2
TFEB Transcription factor EB Human Protein Binding 7942 P19484
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