Expansion of the clinical and molecular spectrum of <i>WWOX</i>‐related epileptic encephalopathy

Chong, Shuk Ching; Cao, Ye; Fung, Eva; Kleppe, Soledad; Gripp, Karen W.; Hertecant, Jozef; El‐Hattab, Ayman W.; Suleiman, Jehan; Clark, Gary D.; Allmen, Gretchen Von; Rodziyevska, Olga; Lewis, Richard A.; Rosenfeld, Jill A.; Dong, Jie; Wang, Xia; Miller, Marcus J.; Bi, Weimin; Liu, Pengfei; Scaglia, Fernando

doi:10.1002/ajmg.a.63074

Cited by 4 publications

(4 citation statements)

References 40 publications

(68 reference statements)

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“…Moreover, literature data on in vivo studies suggest that WWOX in murine models has a crucial role in biological processes such as growth or metabolism, and that its loss leads to enhanced cancer stemness [ 69 , 70 ]. Recent molecular and clinical analyses of WWOX functions have emphasized its role in the modulation of signaling pathways related to cancer promotion, metabolism, CNS development, and neurological diseases [ 10 , 70 , 71 , 72 ]. Furthermore, our previous in silico study proved that the WWOX is associated with complex protein networks, highlighting its direct and indirect function in maintaining cell homeostasis in GBM [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Kałuzińska

Kośla

Kołat

et al. 2023

Biology

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Following the discovery of WWOX, research has moved in many directions, including the role of this putative tumor suppressor in the central nervous system and related diseases. The task of determining the nature of WWOX in glioblastoma (GBM) is still considered to be at the initial stage; however, the influence of this gene on the GBM malignant phenotype has already been reported. Because most of the available in vitro research does not consider several cellular GBM models or a wide range of investigated biological assays, the present study aimed to determine the main processes by which WWOX exhibits anticancer properties in GBM, while taking into account the phenotypic heterogeneity between cell lines. Ectopic WWOX overexpression was studied in T98G, DBTRG-05MG, U251MG, and U87MG cell lines that were compared with the use of assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, three-dimensional and anchorage-independent growth, and invasiveness. Observations presenting the antineoplastic properties of WWOX were consistent for T98G, U251MG, and U87MG. Increased proliferation and tumor growth were noted in WWOX-overexpressing DBTRG-05MG cells. A possible explanation for this, arrived at via bioinformatics tools, was linked to the TARDBP transcription factor and expression differences of USP25 and CPNE2 that regulate EGFR surface abundance. Collectively, and despite various cell line-specific circumstances, WWOX exhibits its anticancer nature mainly via a reduction of cell viability and invasiveness of glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Kałuzińska

Kośla

Kołat

et al. 2023

Biology

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“…WOREE syndrome is characterized by early onset, epilepsy, growth retardation, delayed psychomotor development, and progressive microcephaly. Early-onset epilepsy is a core feature of the neurological phenotype of WOREE syndrome, which is associated with a high premature death rate [14]. In this study, we describe a child from an unrelated Chinese family who presented with growth retardation, early seizure disorder at birth, and followed by global developmental delay.…”

Section: Discussionmentioning

confidence: 97%

Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome

Dong,

Wen,

Zhang

et al. 2023

BMC Med Genomics

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Background Biallelic loss-of-function variants in WWOX cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 affected individuals to date. In this study, we report on an affected individual with WOREE syndrome who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the affected individual, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exome sequencing, quantitative real-time polymerase chain reaction (qPCR), and whole-genome sequencing, to identify the genetic variants. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exome sequencing revealed homozygous exon 6 deletion in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the parents were heterozygous carriers of exon 6 deletion. However, using whole-genome sequencing, we identified three larger deletions (maternal allele with exon 6–8 deletion and paternal allele with two deletions in proximity one in intron 5 and the other in exon 6) involving the WWOX gene in the proband, with deletion sizes of 13,261 bp, 53,904 bp, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6–8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.

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“…WOREE syndrome is characterized by early onset, epilepsy, growth retardation, delayed psychomotor development, and progressive microcephaly. Earlyonset epilepsy is a core feature of the neurological phenotype of WOREE syndrome, which is associated with a high early death rate 14 . In this study, we describe a child from an unrelated Chinese family who presented with growth retardation, early seizure disorder at birth, and followed by global developmental delay.…”

Section: Discussionmentioning

confidence: 99%

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

Dong

Wen

Zhang

et al. 2023

Preprint

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Background WWOXbiallelic and loss-of-function pathogenic variants cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 patients to date. In this study, we report on a WOREE syndrome patient who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the patient, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exon sequencing, quantitative real-time polymerase chain reaction (PCR), and whole-genome sequencing, to identify the genetic defects. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exon sequencing revealed homozygous exon 6 deletions in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the deletions were inherited from each parent. However, using whole-genome sequencing, we identified three larger deletions (intron 5, exon 6, and exon 6-8) involving the WWOX gene in the proband, with deletion sizes of 13,261, 53,904, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6-8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.

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Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Cited by 4 publications

References 40 publications

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome

Identification of compound heterozygous deletions in the WWOX gene caused WOREE syndrome by whole exome sequencing

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