Journal article
High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicates ZFHX3 in epilepsy
Journal of neurogenetics, Vol.32(2), pp.92-105
04/03/2018
DOI: 10.1080/01677063.2018.1445247
PMCID: PMC6122958
PMID: 29718741
Abstract
Epilepsy, which affects ∼1% of the population, is caused by abnormal synchronous neural activity in the central nervous system (CNS). While there is a significant genetic contribution to epilepsy, the underlying causes for the majority of genetic cases remain unknown. The NIH Undiagnosed Diseases Project (UDP) utilized exome sequencing to identify genetic variants in patients affected by various conditions with undefined etiology, including epilepsy. Confirming the functional relevance of the candidate genes identified by exome sequencing in a timely manner is crucial to translating exome data into clinically useful information. To this end, we developed a high throughput version of a seizure-sensitivity assay in zebrafish (Danio rerio) to rapidly evaluate candidate genes found by exome sequencing. We developed open access software, Studying Epilepsy In Zebrafish using R (SEIZR), to efficiently analyze the data. SEIZR was validated by disrupting function of a known epilepsy gene, prickle 1. Next, using SEIZR, we analyzed a candidate gene from the UDP screen (Zinc Finger Homeobox 3, ZFHX3), and showed that reduced ZFHX3 function in zebrafish results in a significant hyperactive response to the convulsant drug pentylenetetrazol (PTZ). We find that ZFHX3 shows strong expression in the CNS during neurogenesis including in the pallium, thalamus, tegmentum, reticular formation, and medulla oblongata - all regions which have roles in motor control and coordination. Our findings in the zebrafish confirm human ZFHX3 is a strong candidate for further neurological studies. We offer SEIZR to other researchers as a tool to rapidly and efficiently analyze large behavioral data sets.
Details
- Title: Subtitle
- High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicates ZFHX3 in epilepsy
- Creators
- Tyson D Fuller - Interdisciplinary Graduate Program in Genetics, University of IowaTrudi A Westfall - Department of Biology, University of IowaTirthasree Das - Department of Biology, University of IowaDeborah V Dawson - Department of Biostatistics, University of IowaDiane C Slusarski - Department of Biology, University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of neurogenetics, Vol.32(2), pp.92-105
- DOI
- 10.1080/01677063.2018.1445247
- PMID
- 29718741
- PMCID
- PMC6122958
- NLM abbreviation
- J Neurogenet
- ISSN
- 0167-7063
- eISSN
- 1563-5260
- Publisher
- Taylor & Francis
- Grant note
- University of Iowa R21 GM110302-02; T32GM008629 / National Institutes of Health
- Language
- English
- Date published
- 04/03/2018
- Academic Unit
- Iowa Neuroscience Institute; Biostatistics; Biology; Pediatric Dentistry; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984070516002771
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