Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy

Breton, Vanessa L.; Aquilino, Mark S.; Repudi, Srinivasarao; Saleem, Afifa; Mylvaganam, Shanthini; Abu-Swai, Sara; Bardakjian, Berj L.; Aqeilan, Rami I.; Carlen, Peter L.

doi:10.1016/j.nbd.2021.105529

Cited by 6 publications

(5 citation statements)

References 69 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…WWOX is a putative tumor suppressor that encodes a member of the short-chain dehydrogenases/reductase (SDR) protein family, which is also related to epileptic encephalopathy ( Johannsen et al, 2018 ; Repudi et al, 2021 ). WWOX plays an essential role in balancing neocortical excitability, and its deletion can lead to spontaneous seizures in mice ( Breton et al, 2021 ). During neurogenesis and early brain development, loss of WWOX can affect different cytoskeletal components and alter prenatal cortical development ( Iacomino et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

Yang¹,

Mao²,

Wang³

et al. 2023

Zoological Research

View full text Add to dashboard Cite

The common marmoset ( Callithrix jacchus ) has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies. Epileptic marmosets have been independently reported in two Asian primate research centers. Nevertheless, the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated. Here, we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing. We identified 14 558 184 single nucleotide polymorphisms (SNPs) from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples. Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers. In addition, SNP and copy number variation (CNV) analyses suggested that the WW domain-containing oxidoreductase ( WWOX ) and Tyrosine-protein phosphatase nonreceptor type 21 ( PTPN21 ) genes may be associated with epilepsy in marmosets. Notably, KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets. This study provides valuable population genomic resources for marmosets in two Asian primate centers. Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers, while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.

show abstract

Section: Discussionmentioning

confidence: 99%

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

Yang¹,

Mao²,

Wang³

et al. 2023

Zoological Research

View full text Add to dashboard Cite

show abstract

“…Indepth analysis of WWOX function in the brain is ongoing. Studies in the WWOX knockout mouse model have demonstrated spontaneous bursts of activity in the neocortex, suggesting that WWOX plays a fundamental role in balancing neocortical excitability 17 An exon 6 deletion and an intron 5 deletion were both found on a single allele, suggesting that the chromosome underwent two separate breakage and rearrangement events. This also re ects the WWOX gene encompassing FRA16D from introns 5 to 8, indicating that the WWOX gene is prone to breakages and rearrangements.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…In-depth analysis of WWOX function in the brain is ongoing. Studies in the WWOX knockout mouse model have demonstrated spontaneous bursts of activity in the neocortex, suggesting that WWOX plays a fundamental role in balancing neocortical excitability [17]. WWOX is a hot spot for both germline and somatic copy number variants.…”

Section: Discussionmentioning

confidence: 99%

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

Dong,

Wen,

Zhang

et al. 2023

BMC Med Genomics

View full text Add to dashboard Cite

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.

show abstract

Altered neocortical oscillations and cellular excitability in an in vitro Wwox knockout mouse model of epileptic encephalopathy

Cited by 6 publications

References 69 publications

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

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

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

Contact Info

Product

Resources

About