Phenotypic analysis of catastrophic childhood epilepsy genes

Commun Biol. 2021 Jun 3;4(1):680. doi: 10.1038/s42003-021-02221-y.

Abstract

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Child
  • Disease Models, Animal*
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism*
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Epilepsy / physiopathology
  • Exome Sequencing / methods
  • Gene Expression
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Larva / genetics
  • Mutation
  • Phenotype
  • Survival Analysis
  • Zebrafish / embryology
  • Zebrafish / genetics*
  • Zebrafish Proteins / genetics*

Substances

  • Zebrafish Proteins
  • Green Fluorescent Proteins