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Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview

The Genetic Institute, Kaplan Medical Center, Hebrew University-Hadassah Medical School, Rehovot 76100, Israel
The Rina Mor Genetic Institute, Wolfson Medical Center, Holon 58100, Israel
The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
Faculty of Medicine and Health, School of Medical Sciences and Discipline of Child and Adolescent Health, The University of Sydney, Westmead 2145, NSW, Australia
Translational Vectorology Research Unit, Children’s Medical Research Institute, The University of Sydney, Westmead 2145, NSW, Australia
Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland
Molecular Neurobiology Research Laboratory, Kids Research, Children’s Hospital at Westmead and The Children’s Medical Research Institute, Westmead 2145, NSW, Australia
Kids Neuroscience Centre, Kids Research, Children’s Hospital at Westmead, Westmead 2145, NSW, Australia
Krembil Research Institute, University Health Network and Department of Medicine, Physiology and BME, University of Toronto, Toronto, ON M5T 1M8, Canada
Author to whom correspondence should be addressed.
These authors contributed to this work equally.
Academic Editor: Edor Kabashi
Cells 2021, 10(4), 824;
Received: 11 March 2021 / Revised: 30 March 2021 / Accepted: 1 April 2021 / Published: 7 April 2021
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations. View Full-Text
Keywords: WOREE; DEE28; SCAR12; WWOX; epilepsy; personalized medicine WOREE; DEE28; SCAR12; WWOX; epilepsy; personalized medicine
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MDPI and ACS Style

Banne, E.; Abudiab, B.; Abu-Swai, S.; Repudi, S.R.; Steinberg, D.J.; Shatleh, D.; Alshammery, S.; Lisowski, L.; Gold, W.; Carlen, P.L.; Aqeilan, R.I. Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview. Cells 2021, 10, 824.

AMA Style

Banne E, Abudiab B, Abu-Swai S, Repudi SR, Steinberg DJ, Shatleh D, Alshammery S, Lisowski L, Gold W, Carlen PL, Aqeilan RI. Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview. Cells. 2021; 10(4):824.

Chicago/Turabian Style

Banne, Ehud, Baraa Abudiab, Sara Abu-Swai, Srinivasa R. Repudi, Daniel J. Steinberg, Diala Shatleh, Sarah Alshammery, Leszek Lisowski, Wendy Gold, Peter L. Carlen, and Rami I. Aqeilan. 2021. "Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview" Cells 10, no. 4: 824.

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