&lt;b&gt;&lt;i&gt;TOP3B&lt;/i&gt;&lt;/b&gt;: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?

Daghsni, Marwa; Lahbib, Saida; Fradj, Mohamed Kacem Ben; Sayeb, Marwa; Kelmemi, Wided; Kraoua, Lilia; Kchaou, Mariem; Mâazoul, Faouzi; Echebbi, S.; Ali, Nadia; Abdelhak, Sonia; Mrad, Ridha

doi:10.1159/000486945

Cited by 16 publications

(14 citation statements)

References 24 publications

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“…Indeed, the TOP3B gene resides on chromosome 22q11.2 in the human genome, a region frequently affected by deletions or duplications leading to congenital heart disease, facial malformation and cognitive dysfunction (68,(161)(162)(163)(164)(165). Consistent with this, copy number variants and de novo mutations in TOP3B have been linked to an increased risk of neurodevelopmental and cognitive disorders, including autism and schizophrenia (68,(166)(167)(168)(169). The involvement of TOP3B in cognition is likely conserved across species because TOP3B has been shown to be essential for correct synaptic formation in both mice and flies (67,166).…”

Section: Roles Of Top3b In Rna Metabolismmentioning

confidence: 88%

The many lives of type IA topoisomerases

Bizard

Hickson

2020

Journal of Biological Chemistry

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The double helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to open for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of Bform DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes.

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Section: Roles Of Top3b In Rna Metabolismmentioning

confidence: 88%

The many lives of type IA topoisomerases

Bizard

Hickson

2020

Journal of Biological Chemistry

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“…CACNA2D2 is an important epilepsy-related calcium channel protein involved in small molecule ligand interactions as well as neuronal cell death pathways [ 30 ] VWF is involved in inflammation, seizures, neurodegeneration, and blood brain barrier permeability [ 34 , 35 ]. Thrombospondin-1 (THBS1) and DNA topoisomerase 3-beta-1 (TOP3B), proteins reported to be associated with various forms of epilepsy [ 31 , 33 , 55 ], were also over-represented in SCG patients compared with IE [ 31 , 33 , 55 ]. Other notable findings included higher observation in the IE group compard to the SCG group of SLIT2 (Slit Guidance Ligand 2 protein), an extracellular matrix protein and member of the SLIT family of proteins which has a role(s) in the blood brain barrier (BBB) integrity [ 37 , 56 ] The mitochondrial protein MT-ND1 with epilepsy background was also found to be observed more in the IE group compared to the SCG group (40).…”

Section: Discussionmentioning

confidence: 99%

“…A PubMed/Medline literature search showed 53% of these differentially expressed proteins were related to neurological function, 36% to immune/inflammation, and 19% to seizures. Notable epilepsy/seizure related proteins (shaded cells in Table 3) include CACNA2D2 [30], THBS1 [31], VLDLR [30,32], THBS1 [31], VLDLR [32], TOP3B [33], VWF [34,35], KIF1A [36], SLIT2 [37], MT-ND1 [38], EPHB2 [39], OCA2 [40], AKAP11 [41], ADAM11 [42], MAOB [43], and VPS13D [44].…”

Section: Plos Onementioning

confidence: 99%

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

et al. 2020

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A major source of epilepsy is Neurocysticercosis (NCC), caused by Taenia solium infection. Solitary cysticercus granuloma (SCG), a subgroup of NCC induced epilepsy, is the most common form of NCC in India. Current diagnostic criteria for SCG epilepsy require brain imaging which may not be available in communities where the disease is endemic. Identification of serum changes and potential biomolecules that could distinguish SCG epilepsy from idiopathic generalized epilepsy (IE), without the initial need for imaging, could assist in disease identification, understanding, and treatment. The objective here was to investigate, using mass spectrometry (MS), sera biomolecule differences between patients with SCG epilepsy or IE to help distinguish these disorders based on physiological differences, to understand underlying phenotypes and mechanisms, and to lay ground work for future therapeutic and biomarker analyses. Sera were obtained from patients with SCG or IE (N = 29 each group). Serum mass peak profiling was performed with electrospray ionization (ESI) MS, and mass peak area means in the two groups were compared using leave one [serum sample] out cross validation (LOOCV). Serum LOOCV analysis identified significant differences between SCG and IE patient groups (p = 10 −20), which became non-significant (p = 0.074) when the samples were randomly allocated to the groups and reanalyzed. Tandem MS/MS peptide analysis of serum mass peaks from SCG or IE patients was performed to help identify potential peptide/protein biochemical and phenotypic changes involving these two forms of epilepsy. Bioinformatic analysis of these peptide/protein changes suggested neurological, inflammatory, seizure, blood brain barrier, cognition, ion channel, cell death, and behavior related biochemical systems were being altered in these disease states. This

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“…Thus, the impaired function of Top3β in heterochromatin and transposon silencing may contribute to the aging phenotype in the knockout mice. In human, Top3β mutations have been linked to neurological and mental disorders, including: schizophrenia, autism, epilepsy, intellectual disability, and cognitive impairment [11,91,92,93,94], suggesting that Top3β mutations may cause neurological defects. Similarly, mouse and Drosophila with Top3β mutations also show abnormal synapse formation [8].…”

Section: Importance Of Topoisomerase Function In Heterochromatinmentioning

confidence: 99%

Roles of Topoisomerases in Heterochromatin, Aging, and Diseases

Lee

Wang

2019

Genes

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Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin can cause the de-repression of genes and transposons, leading to deleterious physiological changes such as aging, cancer, and neurological disorders. While the roles of topoisomerases in many DNA-based processes have been investigated and reviewed, their roles in heterochromatin formation and function are only beginning to be understood. In this review, we discuss recent findings on how topoisomerases can promote heterochromatin organization and impact the transcription of genes and transposons. We will focus on two topoisomerases: Top2α, which catenates and decatenates double-stranded DNA, and Top3β, which can change the topology of not only DNA, but also RNA. Both enzymes are required for normal heterochromatin formation and function, as the inactivation of either protein by genetic mutations or chemical inhibitors can result in defective heterochromatin formation and the de-silencing of transposons. These defects may contribute to the shortened lifespan and neurological disorders observed in individuals carrying mutations of Top3β. We propose that topological stress may be generated in both DNA and RNA during heterochromatin formation and function, which depend on multiple topoisomerases to resolve.

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<b><i>TOP3B</i></b>: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?

Cited by 16 publications

References 24 publications

The many lives of type IA topoisomerases

The many lives of type IA topoisomerases

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

Roles of Topoisomerases in Heterochromatin, Aging, and Diseases

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