Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function of<i>kif2a</i>in Zebrafish

Partoens, Michèle; Meulemeester, Ann-Sofie De; Giong, Hoi-Khoanh; Pham, Duc-Hung; Lee, Jeong-Soo; Witte, Peter de; Siekierska, Aleksandra

doi:10.1523/eneuro.0055-21.2021

Cited by 8 publications

(3 citation statements)

References 57 publications

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“…Thus, our findings support that the interruption of ATP microtubule binding would lead to a non‐functional KIF2A (Poirier et al, 2013 ). KIF2A is an ATP‐driven microtubule‐associated protein that uses the energy of ATP hydrolysis to carry out mechanical work along microtubule tracks (Ali & Yang, 2020 ; Poirier et al, 2013 ), and, in zebrafish larvae, kif2a knockout resulted in reduced head size and neuronal loss in the brain due to a decrease in cell proliferation and increased levels of cell apoptosis (Partoens et al, 2021 ), which supported the ATP‐driven function theory.…”

Section: Discussionmentioning

confidence: 92%

Mutations obstructing ATP's emplacement in KIF2A nucleotide‐binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability

Zhao

Chen

et al. 2023

Molec Gen & Gen Med

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BackgroundKIF2A‐related tubulinopathy (MIM: #615411) is a very rare disorder that was clinically characterized as microcephaly, epilepsy, motor developmental disorder (MDD), and various malformations of cortical development, but intellectual disability (ID) or global developmental delay (GDD) was rarely reported in the patients.MethodsQuad whole‐exome sequencing (WES) was performed on the proband, the older brother, and their parents. Sanger sequencing was used to verify the candidate gene variant.ResultsThe proband, a 23‐month‐old boy, was previously diagnosed with GDD, and his brother, aged nine years, had ID; both were born to a healthy couple. Quad‐WES detected a novel heterozygous KIF2A variant, c.1318G>A (p.G440R), in both the brothers but not in the parents. In‐silico analysis revealed that the variants G440R and G318R (which were previously reported in the only reported patient with GDD) lead to markedly enlarged side chains and hinder ATP's emplacement in the NBD pocket.ConclusionsThe type of KIF2A variants that sterically hinder ATP emplacing in KIF2A NBD pocket may be associated with the intellectual disability phenotype; however, further studies are needed. Findings in this case also suggest a rare parental germline mosaicism of KIF2A G440R.

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Section: Discussionmentioning

confidence: 92%

Mutations obstructing ATP's emplacement in KIF2A nucleotide‐binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability

Zhao

Chen

et al. 2023

Molec Gen & Gen Med

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“…Hematoxylin and eosin staining was performed on 6 dpf larvae as described previously ( Siekierska et al, 2019 ; Partoens et al, 2021 ). Larvae were anesthetized in 0.008% tricaine and fin clipped for genotyping.…”

Section: Methodsmentioning

confidence: 99%

Connectivity Mapping Using a Novel sv2a Loss-of-Function Zebrafish Epilepsy Model as a Powerful Strategy for Anti-epileptic Drug Discovery

Zhang

Heylen

Partoens

et al. 2022

Front. Mol. Neurosci.

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Synaptic vesicle glycoprotein 2A (SV2A) regulates action potential-dependent neurotransmitter release and is commonly known as the primary binding site of an approved anti-epileptic drug, levetiracetam. Although several rodent knockout models have demonstrated the importance of SV2A for functional neurotransmission, its precise physiological function and role in epilepsy pathophysiology remains to be elucidated. Here, we present a novel sv2a knockout model in zebrafish, a vertebrate with complementary advantages to rodents. We demonstrated that 6 days post fertilization homozygous sv2a–/– mutant zebrafish larvae, but not sv2a+/– and sv2a+/+ larvae, displayed locomotor hyperactivity and spontaneous epileptiform discharges, however, no major brain malformations could be observed. A partial rescue of this epileptiform brain activity could be observed after treatment with two commonly used anti-epileptic drugs, valproic acid and, surprisingly, levetiracetam. This observation indicated that additional targets, besides Sv2a, maybe are involved in the protective effects of levetiracetam against epileptic seizures. Furthermore, a transcriptome analysis provided insights into the neuropathological processes underlying the observed epileptic phenotype. While gene expression profiling revealed only one differentially expressed gene (DEG) between wildtype and sv2a+/– larvae, there were 4386 and 3535 DEGs between wildtype and sv2a–/–, and sv2a+/– and sv2a–/– larvae, respectively. Pathway and gene ontology (GO) enrichment analysis between wildtype and sv2a–/– larvae revealed several pathways and GO terms enriched amongst up- and down-regulated genes, including MAPK signaling, synaptic vesicle cycle, and extracellular matrix organization, all known to be involved in epileptogenesis and epilepsy. Importantly, we used the Connectivity map database to identify compounds with opposing gene signatures compared to the one observed in sv2a–/– larvae, to finally rescue the epileptic phenotype. Two out of three selected compounds rescued electrographic discharges in sv2a–/– larvae, while negative controls did not. Taken together, our results demonstrate that sv2a deficiency leads to increased seizure vulnerability and provide valuable insight into the functional importance of sv2a in the brain in general. Furthermore, we provided evidence that the concept of connectivity mapping represents an attractive and powerful approach in the discovery of novel compounds against epilepsy.

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“…Hierbij wordt een onderscheid gemaakt tussen chemische, elektrische en genetische modellen (Löscher, 2011). Voor een snelle en kostenefficiënte geneesmiddelenontdekking, worden echter ook niet-zoogdiermodellen, zoals de zebravis en drosophila ontwikkeld en gevalideerd (Partoens et al, 2021).…”

Section: De Zebravis Als Epilepsiemodelunclassified

Epilepsie-onderzoek: from bed to bench and back to bed?

Sourbron¹,

Lagae²

2022

Epilepsie

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De hoeksteen van epilepsiebehandeling is het gebruik van anticonvulsieve medicijnen. Echter, niet iedere patiënt wordt aanvalsvrii met de bestaande medicijnen. Hierdoor is onderzoek naar anticonvulsieve medicijnen met unieke werkingsmechanismen nog steeds noodzakelijk. Er zijn verscheidene strategieën mogelijk bij de zoektocht naar dergelijke middelen, waarbij translatie en back-translatie kunnen bijdragen aan nieuwere, innovatieve anticonvulsieve medicijnen voor patiënten met epilepsie wereldwijd.

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Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function ofkif2ain Zebrafish

Abstract: PdW initiated the project and the line was generated by DHP. The project was further coordinated by MP and AS. WISH, western blot, survival, head and brain measurements, histological experiments, 2 locomotor and cognition assay, local field potential recordings and qPCR were performed and

Cited by 8 publications

References 57 publications

Mutations obstructing ATP's emplacement in KIF2A nucleotide‐binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability

Mutations obstructing ATP's emplacement in KIF2A nucleotide‐binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability

Connectivity Mapping Using a Novel sv2a Loss-of-Function Zebrafish Epilepsy Model as a Powerful Strategy for Anti-epileptic Drug Discovery

Epilepsie-onderzoek: from bed to bench and back to bed?

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