WWOX
protein-codingWW domain containing oxidoreductase, the group of Short chain dehydrogenase/reductase superfamily
Gene summary
This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1,113.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013687
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100062
Submitter: ClinGen
*WWOX* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE; MONDO:0100062) in 2014 (Abdel-Salam et al., PMID: 24456803). Patients often present with seizures and other phenotypes including: global developmental delay, intellectual disability, microcephaly, and hypotonia. Of note, an assertion has also been made for a relationship between *WWOX* and spinocerebellar ataxia (OMIM:614322). At the time of curation, there were few cases of individuals with variants in *WWOX* and spinocerebellar ataxia available in the literature. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern, and little difference in phenotypic variability between DEE and spinocerebellar ataxia in patients with *WWOX* variants. Given the evidence available at this time, the group feels that spinocerebellar ataxia fits best as part of a broader spectrum of disease, rather than a distinct gene-disease relationship. Therefore, we have lumped these cases into one curation for autosomal recessive DEE (MONDO:0100062). Eleven variants (missense, nonsense, frameshift, splice-site, deletions) reported in nine probands in four publications are included in this curation (PMIDs: 24456803, 24369382, 25411445, 30853297). Of note, some cases in Mignot et al. (2015, PMID: 25411445) include copy number variants that cannot yet be scored in the GCI. For that reason, they are detailed here in the evidence summary. We have scored the compound heterozygous multi-exon deletions in exons 1-5 and 6-8 reported in patient 1 at 1 point each. Patient 2 was reported to have a deletion spanning exon 6, along with a p.Trp335* nonsense variant (ClinVar: 180249), both scored at 1 point. This additional evidence therefore adds 4 points to the genetic evidence category. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The gene-disease relationship is also supported by an animal model (PMIDs: 24369382). In summary, there is a definitive relationship between *WWOX* and autosomal recessive DEE (MONDO:0100062). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 3, 2021 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0013687
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013687
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014533
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016674
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014533
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013687
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014533
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013687
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014533
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WWOX variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016373.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 229 | 3 | 237 | ||
| missense | 3 | 17 | 420 | 26 | 7 | 473 |
| nonsense | 15 | 15 | 3 | 33 | ||
| start loss | 2 | 2 | ||||
| frameshift | 12 | 9 | 4 | 25 | ||
| splice donor/acceptor (+/-2bp) | 11 | 17 | 1 | 29 | ||
| Total | 43 | 58 | 433 | 255 | 10 | 799 |
Highest pathogenic variant AF is 0.00013014459
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057457.1 | 9 | MANE Select | |
| Ensembl | ENSP00000457230.1 | 9 | MANE Select | |
| RefSeq | NP_001278926.1 | 6 | Standard | |
| RefSeq | NP_570607.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| wwox | Danio rerio | Structure: whole organism Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
- p73 transcription factor network
Biological Process
- negative regulation of transcription by RNA polymerase II
- osteoblast differentiation
- steroid metabolic process
- Wnt signaling pathway
- negative regulation of Wnt signaling pathway
Molecular Function
- transcription coactivator activity
- protein binding
- oxidoreductase activity
- enzyme binding
- protein dimerization activity
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000566780
- Coding exons
- 9
- Length
- 1113255
- Individuals with no LoFs
- 124748
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 53
- Defined
- 124801
- p
- 0.000212
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -4.44 | 435 | 241 | 1.81 | 0.0000154 | 2682 |
| Missense (PolyPhen) | 101 | 62.247 | 1.6226 | 748 | ||
| Synonymous | -6.24 | 170 | 93.3 | 1.82 | 0.00000660 | 813 |
| Loss of Function | -0.311 | 22 | 20.5 | 1.07 | 0.00000105 | 229 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00019 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00028 | 0.00028 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00021 | 0.00021 | rare |
| South Asian | 0.00043 | 0.00042 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development (By similarity). May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm. {ECO:0000250, ECO:0000269|PubMed:11719429, ECO:0000269|PubMed:15070730, ECO:0000269|PubMed:15548692, ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:16219768, ECO:0000269|PubMed:19366691, ECO:0000269|PubMed:19465938}.;
- Disease
- DISEASE: Note=Defects in WWOX may be involved in several cancer types. The gene spans the second most common chromosomal fragile site (FRA16D) which is frequently altered in cancers (PubMed:10861292). Alteration of the expression and expression of some isoforms is associated with cancers. However, it is still unclear if alteration of WWOX is directly implicated in cancerogenesis or if it corresponds to a secondary effect (PubMed:10861292, PubMed:11572989, PubMed:15266310, PubMed:15073125, PubMed:15131042). {ECO:0000269|PubMed:10861292, ECO:0000269|PubMed:11572989, ECO:0000269|PubMed:15073125, ECO:0000269|PubMed:15131042, ECO:0000269|PubMed:15266310}.; DISEASE: Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. {ECO:0000269|PubMed:11956080}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia, autosomal recessive, 12 (SCAR12) [MIM:614322]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR12 is additionally characterized by onset of generalized seizures in infancy, and delayed psychomotor development with mental retardation. Some patients may also show spasticity. {ECO:0000269|PubMed:24369382, ECO:0000269|PubMed:24456803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 28 (EIEE28) [MIM:616211]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25411445}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.982
Intolerance Scores
- LoFtool
- 0.304
- RVIS EVS
- 1.1
- RVIS percentile EVS
- 91.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.445
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | Medium |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |