A novel missense variant in the SDR domain of the WWOX gene leads to complete loss of WWOX protein with early-onset epileptic encephalopathy and severe developmental delay.

The human WWOX (WW domain-containing oxidoreductase) gene, originally known as a tumor suppressor gene, has been shown to be important for brain function and development. In recent years, mutations in WWOX have been associated with a wide phenotypic spectrum of autosomal recessively inherited neurodevelopmental disorders. Whole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. Functional WWOX analysis was performed in fibroblasts of one patient. Transcription and translation were assessed by quantitative real-time PCR and Western blotting. We report two related patients who presented with early epilepsy refractory to treatment, progressive microcephaly, profound developmental delay, and brain MRI abnormalities. Additionally, one of the patients showed bilateral optic atrophy. Whole exome sequencing revealed homozygosity for a novel missense variant affecting the evolutionary conserved amino acid Gln230 in the catalytic short-chain dehydrogenase/reductase (SDR) domain of WWOX in both girls. Functional studies showed normal levels of WWOX transcripts but absence of WWOX protein. To our knowledge, our patients are the first individuals presenting the more severe end of the phenotypic spectrum of WWOX deficiency, although they were only affected by a single missense variant of WWOX. This could be explained by the functional data indicating an impaired translation or premature degradation of the WWOX protein.

Expression and Clinical Significance of WWOX Protein and BCL-2 Protein in Primary Lung Cancer / 现代检验医学杂志

Objective Toexplore expression and clinical significance of WWOX protein and the Bcl-2 protein in the organiza-tion of bronchial lung cancer (primary lung cancer).Methods Chose 76 lung cancer patients with clear pathological diagno-sis who were hospitalized in the Shaanxi Provincial People’s Hospital from 2010 and 2015(including 29 cases of adenocarci-noma,27 cases of squamous cell carcinoma,and 20 cases of small cell carcinoma)and 7 cases of normal lung tissue,8 cases of lung tuberculosis.The expressions of WWOX protein,Bcl-2 protein and more that 5 cm normal lung tissue adjacent to carci-noma were measured by immunohistochemistry SP method.The expression difference between patients and normal control group and the influence of sex,age,pathological type,differentiation degree,clinical stage,lymph node metastasis,smoking index on the expression of WWOX protein and Bcl-2 protein in lung cancer were analyzed.Results ①The positive expres-sion rate of WWOX protein in lung cancer group (35.52%)was significantly lower than that in normal lung tissue (73.33%,P<0.05).The positive expression rate of Bcl-2 protein in lung cancer group (78.06%)was significantly higher than that in control group (23.75%,P<0.05 ).②The positive expression rate of WWOX protein in male patients (21.43%)was significantly lower than that in female patients (52.94%),and the difference was statistically significant (χ2=8.146,P=0.04).The positive expression rate of Bcl-2 protein in male patients (71.43%)was significantly higher than that in female patients (35.29%),the difference was statistically significant (χ2=9.923,P=0.002).③In lung cancer with lymph node metastasis,the positive rate of WWOX protein (17.07%)was significantly lower than that in non-lymph node metastasis (48.57%),and the difference was statistically significant (χ2=8.67,P=0.003).In lung cancer with lymph node metastasis,the positive rate of Bcl-2 protein expression (68.29%)was significantly higher than that in non-lymph node me-tastasis (34.28%),and the difference was statistically significant (χ2=8.758,P=0.003).④The positive rate of expression of WWOX protein in patients whose smoking index≥400 and in patients that<400 was 15.63% and 47.73%,respectively, the differences were significant (χ2=8.48,P=0.003).The positive rate of expression of Bcl-2 protein in patients whose smoking index≥400 and in patients that<400 was 56.25% and 22.73%,respectively,the differences were significant (χ2=8.947,P=0.003).⑤WWOX and Bcl-2 protein expressions had no obvious relationship with ages,pathological type,degree of differentiation and clinical stage.⑥WWOX protein expression had negative correlation with Bcl-2 protein expression in lung cancr tissues.Conclusion WWOX protein expression in lung cancer was lower than that in adjacent normal lung tis-sue,Bcl-2 protein expression in lung cancer tissues was higher than that in adjacent normal lung tissue.WWOX protein ex-pression had negative correlation with Bcl-2 protein expression in lung cancer tissues.

The WWOX gene modulates high-density lipoprotein and lipid metabolism.

BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol constitutes a major risk factor for atherosclerosis. Recent studies from our group reported a genetic association between the WW domain-containing oxidoreductase (WWOX) gene and HDL cholesterol levels. Here, through next-generation resequencing, in vivo functional studies and gene microarray analyses, we investigated the role of WWOX in HDL and lipid metabolism. METHODS AND RESULTS: Using next-generation resequencing of the WWOX region, we first identified 8 variants significantly associated and perfectly segregating with the low-HDL trait in 2 multigenerational French Canadian dyslipidemic families. To understand in vivo functions of WWOX, we used liver-specific Wwox(hep-/-) and total Wwox(-/-) mice models, where we found decreased ApoA-I and Abca1 levels in hepatic tissues. Analyses of lipoprotein profiles in Wwox(-/-), but not Wwox(hep-/-) littermates, also showed marked reductions in serum HDL cholesterol concentrations, concordant with the low-HDL findings observed in families. We next obtained evidence of a sex-specific effect in female Wwox(hep-/-) mice, where microarray analyses revealed an increase in plasma triglycerides and altered lipid metabolic pathways. We further identified a significant reduction in ApoA-I and Lpl and an upregulation in Fas, Angptl4, and Lipg, suggesting that the effects of Wwox involve multiple pathways, including cholesterol homeostasis, ApoA-I/ABCA1 pathway, and fatty acid biosynthesis/triglyceride metabolism. CONCLUSIONS: Our data indicate that WWOX disruption alters HDL and lipoprotein metabolism through several mechanisms and may account for the low-HDL phenotype observed in families expressing the WWOX variants. These findings thus describe a novel gene involved in cellular lipid homeostasis, which effects may impact atherosclerotic disease development.

WWOX gene expression in non-small cell lung cancer and its clinical significance / 西安交通大学学报(医学版)

Objective To study the expression of WWOX gene in non-small cell lung cancer and its significance. Methods WWOX protein expression was evaluated by immunohistochemistry in 81 NSCLC patients(50 squamous cell carcinomas,31 adenocarcinomas and 20 adjacent normal lung tissues),and correlation with histopathologic(histotype,grade,tumor-node-metastasis,stage) and clinical characteristics was studied. Results WWOX expression was absent/reduced in 72.8% of NSCLC,whereas it was normal in 80.0% of adjacent normal lung tissues.WWOX expression was strongly associated with tumor histology and histologic grade(P