Human Gene Module / Chromosome 8 / WWP1

WWP1WW domain containing E3 ubiquitin protein ligase 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 2
Rare Variants / Common Variants
10 / 0
Aliases
WWP1, AIP5,  Tiul1,  hSDRP1
Associated Syndromes
-
Chromosome Band
8q21.3
Associated Disorders
-
Relevance to Autism

Whole-exome sequencing of 198 unrelated individuals with ASD/ID in Novelli et al., 2020 identified eight different heterozygous germline mutations (including one that was recurrent in three unrelated patients) in the WWP1 gene in 10 ASD probands; variants in WWP1 were subsequently shown to be preferentially enriched in ASD/ID probands compared to European populations in gnomAD (p < 0.00001; OR = 30.6 (95% CI 16.27-57.59)) and a cohort of 1158 individuals from the Italian general population (p < 0.00001; OR = 19.93 (95% CI 5.47-72.90)). Two of the missense variants identified in ASD probands in Novelli et al., 2020 (p.Arg86His and p.Asn745Ser) had previously been shown in Lee et al., 2020 to induce increased PTEN polyubiquitination compared to wild-type WWP1, consistent with a gain-of-function effect.

Molecular Function

WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 4 tandem WW domains and a HECT (homologous to the E6-associated protein carboxyl terminus) domain. The encoded protein belongs to a family of NEDD4-like proteins, which are E3 ubiquitin-ligase molecules and regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to WWP1 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition Lee YR et al. (2020) No -
2 Primary WWP1 germline variants are associated with normocephalic autism spectrum disorder Novelli G et al. (2020) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.540-5T>C - intron_variant Familial Maternal - 32699206 Novelli G et al. (2020)
c.1167A>C p.Arg389Ser missense_variant Unknown - - 32699206 Novelli G et al. (2020)
c.2234A>G p.Asn745Ser missense_variant Unknown - - 32699206 Novelli G et al. (2020)
c.257G>A p.Arg86His missense_variant Familial Maternal - 32699206 Novelli G et al. (2020)
c.1583G>A p.Arg528His missense_variant Familial Paternal - 32699206 Novelli G et al. (2020)
c.2176G>A p.Val726Ile missense_variant Familial Maternal - 32699206 Novelli G et al. (2020)
c.2182A>T p.Met728Leu missense_variant Familial Paternal - 32699206 Novelli G et al. (2020)
c.2234A>G p.Asn745Ser missense_variant Familial Maternal - 32699206 Novelli G et al. (2020)
c.2234A>G p.Asn745Ser missense_variant Familial Paternal - 32699206 Novelli G et al. (2020)
c.2678G>A p.Arg893His missense_variant Familial Paternal - 32699206 Novelli G et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49330710030725

Ranking 4204/25841 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 0.95684428383626

Ranking 2575/18225 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 0.86878242952412

Ranking 4243/18665 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 -0.36218654599355

Ranking 17954/20870 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
Submit New Gene

Report an Error