{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:38:19Z","timestamp":1787495899833,"version":"build-2736575974"},"reference-count":31,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T00:00:00Z","timestamp":1546214400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>WWOX<\/jats:italic>\n                    gene has a WW domain containing oxidoreductase, which is located at the common fragile site FRA16D at chromosome 16q23.\n                    <jats:italic>WWOX<\/jats:italic>\n                    is a tumor suppressor gene that has been associated with several types of cancer such as hepatic, breast, lung, prostate, gastric, and ovarian. Recently WWOX has been implicated in epilepsy, where studies show homozygous loss-of-function mutation lead to early-infantile epileptic encephalopathy, spinocerebellar ataxia, intractable seizures and developmental delay, and early lethal microcephaly syndrome with epilepsy. Here we investigate two consanguineous Saudi families and we identified three probands with epileptic encephalopathy. Whole exome sequencing revealed a novel homozygous mutation in the\n                    <jats:italic>WWOX<\/jats:italic>\n                    gene in one proband. In addition, we identified a previously reported\n                    <jats:italic>WWOX<\/jats:italic>\n                    mutation in two probands. Later on these findings were confirmed with Sanger sequencing. The underlying mechanism on how WWOX mutations lead to seizure remains elusive. To date very few\n                    <jats:italic>WWOX<\/jats:italic>\n                    mutations have been associated with neurological disorder and our newly identified mutations support the notion that WWOX play an important role in neurons and will aid in better diagnosis and genetic counseling.\n                  <\/jats:p>","DOI":"10.1515\/tnsci-2018-0029","type":"journal-article","created":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T13:39:42Z","timestamp":1548250782000},"page":"203-208","source":"Crossref","is-referenced-by-count":29,"title":["Novel homozygous mutation in the WWOX gene causes seizures and global developmental delay: Report and review"],"prefix":"10.1515","volume":"9","author":[{"given":"Salleh N.","family":"Ehaideb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majed J.","family":"Al-Bu Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaafer J.","family":"Al-obaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareemah M.","family":"Aljassim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Alfadhel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","reference":[{"key":"ref131","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.molmed.2006.11.006","article-title":"Lai FJ Sheu HM WW domain-containing oxidoreductase: a candidate tumor suppressor","volume":"13","year":"2007","journal-title":"Trends Mol Med"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.neuroscience.2003.12.036","article-title":"Li H Chang NS Expression of WW domain-containing oxidoreductase WOX1 in the developing murine nervous system","volume":"124","year":"2004","journal-title":"Neuroscience"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"17319","DOI":"10.1074\/jbc.M116.716167","article-title":"Wei HL Chang NS Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation","volume":"291","year":"2016","journal-title":"J Biol Chem"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1093\/hmg\/9.11.1651","article-title":"Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells","volume":"9","year":"2000","journal-title":"Hum Mol Genet"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0014-5793(01)03290-2","article-title":"Wiesner S Sudol M WW and SH3 domains, two different scaffolds to recognize proline-rich ligands","volume":"513","year":"2002","journal-title":"FEBS Lett"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"11417","DOI":"10.1073\/pnas.191175898","article-title":"WWOX: a candidate tumor suppressor gene involved in multiple tumor types","volume":"98","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.neuroscience.2004.07.054","article-title":"Hsu LJ Chang NS Light-induced retinal damage involves tyrosine 33 phosphorylation, mitochondrial and nuclear translocation of WW domain-containing oxidoreductase in vivo","volume":"130","year":"2005","journal-title":"Neuroscience"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/brain\/awt338","article-title":"The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation","volume":"137","year":"2014","journal-title":"Brain"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1093\/brain\/awm078","article-title":"A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23","volume":"130","year":"2007","journal-title":"Brain"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.trci.2017.02.001","article-title":"Zfra restores memory deficits in Alzheimer\u2019s disease triple-transgenic mice by blocking aggregation of TRAPPC6ADelta, SH3GLB2, tau, and amyloid beta, and inflammatory NF-kappaB activation","volume":"3","year":"2017","journal-title":"Alzheimers Dement (N Y)"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/jhg.2015.17","article-title":"WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period","volume":"60","year":"2015","journal-title":"J Hum Genet"},{"key":"ref241","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s12881-016-0317-z","article-title":"Kamel H Ben-Omran T W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report","volume":"17","year":"2016","journal-title":"BMC Med Genet"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"4401","DOI":"10.1073\/pnas.0400805101","article-title":"Functional association between Wwox tumor suppressor protein and p73, a p53 homolog","volume":"101","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"8751","DOI":"10.1073\/pnas.87.22.8751","article-title":"Allelic loss of chromosomes 16q and 10q in human prostate cancer","volume":"87","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1002\/ijc.2910510605","article-title":"Accumulation of allelic loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma","volume":"51","year":"1992","journal-title":"Int J Cancer"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1177\/1535370217752350","article-title":"Chang NS Phosphorylation\/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events","volume":"243","year":"2018","journal-title":"Exp Biol Med (Maywood)"},{"key":"ref31","first-page":"2258","article-title":"Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma","volume":"62","year":"2002","journal-title":"Cancer Res"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1750-1172-9-12","article-title":"Swan D Bolz HJ The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration","volume":"9","year":"2014","journal-title":"Orphanet J Rare Dis"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1158\/1078-0432.CCR-03-0096","article-title":"The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis","volume":"10","year":"2004","journal-title":"Clin Cancer Res"},{"key":"ref261","article-title":"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","year":"2018","journal-title":"Neurogenetics"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s12031-014-0463-8","article-title":"Ali BR Al-Gazali L A novel whole exon deletion in WWOX gene causes early epilepsy, intellectual disability and optic atrophy","volume":"56","year":"2015","journal-title":"J Mol Neurosci"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0006-2952(03)00484-2","article-title":"Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses","volume":"66","year":"2003","journal-title":"Biochem Pharmacol"},{"key":"ref11","first-page":"2140","article-title":"Hawkins KA Aldaz CM WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer","volume":"60","year":"2000","journal-title":"Cancer Res"},{"key":"ref81","first-page":"878","article-title":"WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer","volume":"63","year":"2003","journal-title":"Cancer Res"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"11792","DOI":"10.18632\/oncotarget.2961","article-title":"Chang NS Sze CI WW domain-containing oxidoreductase in neuronal injury and neurological diseases","volume":"5","year":"2014","journal-title":"Oncotarget"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1111\/j.1460-9568.2008.06139.x","article-title":"MPP+-induced neuronal death in rats involves tyrosine 33 phosphorylation of WW domain-containing oxidoreductase WOX1","volume":"27","year":"2008","journal-title":"Eur J Neurosci"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1136\/jmedgenet-2014-102748","article-title":"WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation","volume":"52","year":"2015","journal-title":"J Med Genet"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1684\/epd.2017.0924","article-title":"Craiu D Iliescu C Practical clues for diagnosing WWOX encephalopathy","volume":"19","year":"2017","journal-title":"Epileptic Disord"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0898-6568(01)00236-4","article-title":"Sudol M Winder SJ The WW domain: linking cell signalling to the membrane cytoskeleton","volume":"14","year":"2002","journal-title":"Cell Signal"},{"key":"ref291","article-title":"Gedela S Zuccoli G Severe CNS involvement in WWOX mutations: Description of five new cases","year":"2015","journal-title":"Am J Med Genet A 167A: 3209-3213"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1158\/1078-0432.CCR-03-0594","article-title":"Loss of WWOX expression in gastric carcinoma","volume":"10","year":"2004","journal-title":"Clin Cancer Res"}],"container-title":["Translational Neuroscience"],"original-title":[],"link":[{"URL":"http:\/\/www.degruyter.com\/view\/j\/tnsci.2018.9.issue-1\/tnsci-2018-0029\/tnsci-2018-0029.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/tnsci-2018-0029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:45:07Z","timestamp":1619052307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/tnsci-2018-0029\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,31]]},"references-count":31,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.1515\/tnsci-2018-0029","relation":{},"ISSN":["2081-6936"],"issn-type":[{"value":"2081-6936","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,31]]}}}