Analysis of combined CNV data from the Autism Genetic Resource Exchange (AGRE) and the Simons Simplex Collection (SSC) in Leppa et al., 2016 found that CNVs overlapping the WWOX gene were identified in affected children in 12 of 3,565 families (0.34%) but in only one unaffected sibling out of 2,633 families (0.04%, p=0.01, OR=8.8, Fisher's exact test). In contrast, the overall frequency of >100 kb CNVs overlapping WWOX in the Database of Genomic Variants (DGV) was 26/27,263 (0.10%), and the combined association test for all datasets was nominally significant (p=0.0148, OR=2.6).
Molecular Function
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. Biallelic variants in the WWOX gene are responsible for early infantile epileptic encephalopathy-28 (EIEE28; OMIM 616211) and autosomal recessive spinocerebellar ataxia-12 (SCAR12; OMIM 614322).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
The LDE strain (lethal dwarfism with epilepsy) was inbred using heterozygous rats, derived from inbreeding of a closed colony of Wistar Imamichi rats. Mutant rats showed severe dwarfism, short lifespan (early postnatal lethality), and high incidence of epileptic seizures. The lde locus was mapped to a 1.5-Mbp region on rat chromosome 19 that included the latter half of the Wwox gene. The lde/lde rat is unique model for studying the physiological function of Wwox in CNS.
References
Type
Title
Author, Year
Primary
Phenotypic characterization of spontaneously mutated rats showing lethal dwarfism and epilepsy.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
LDE strain (lethal dwarfism with epilepsy) was inbred using heterozygous rats, derived from inbreeding of a closed colony of Wistar Imamichi rats.
Allele Type: Spontaneous mutation
Strain of Origin: Wistar Imamichi LDE
Genetic Background: Wistar Imamichi
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source:
Description: Interictal spikes were sporadically observed in homozygous rats under non-stimulated conditions. Typical EEGs recorded from homozygous rats during audiogenic seizures include 'wild running' (fast waves) and clonic seizure (bursts of spikes).
Exp Paradigm: Electroencephalogram (EEG)
Description: Increased number of apoptotic germ cells and the presences of deciduous germ cells in the center of seminiferous tubules in mutant testes.
Exp Paradigm: Histology
Description: Decreased diameter of seminiferous tubes, decreased number of spermatocytes and no sperm found in mutant testes; smaller size of Sertoli cells
Exp Paradigm: Histology
Description: Decreased levels of FSH and LH compared to male control rats at 4 weeks; at 3 and 5 weeks levels are not significantly different; decreased levels of FH- and LSH-positive cells in the pituitary
Exp Paradigm: Immunostaining: LH and FSH antibodies; Measurement of enzyme activity-Immunostaining
Description: Decreased levels of FSH and LH compared to male control rats at 4 weeks; at 3 and 5 weeks levels are not significantly different; decreased levels of FH- and LSH-positive cells in the pituitary
Exp Paradigm: Immunostaining: LH and FSH antibodies; Measurement of enzyme activity- Measurement of enzyme activity
Description: The testes of mutant males show immature seminiferous tubules with decreased diameter, spindle-shaped mesenchymal Leydig-like cells in the interstitium, and no normal spermatocytes were present in the tubules of mutant rats
Exp Paradigm: Histology
Description: The relative weights of the adrenal and pituitary glands were higher in female mutant rats, and kidney, lungs were also higher in both sexes.
Exp Paradigm: Measurement of tissue weight
Description: Absolute weight of all organs (except the male brain) were decreased in mutant rats. Additionally, the relative weights of testes and spleen in males, and thymus in both sexes was significantly lower.
Exp Paradigm: Measurement of tissue weight
Description: Increased plasma concentrations of urea nitrogen, creatinine in both sexes, and inorganic phosphate in females. The concentrations of electrolytes, aberration enzymes, glucose and triglyceride were comparable to control rats.
Exp Paradigm: In vitro diagnostic tests
Description: No bands for two variants, 47 or 42 kDa were observed in the homozygous mutant, but Wwox mRNA was observed, in testes and hippocampus
Exp Paradigm: Western blot: Wwox antibody
