Mutations in prickle orthologs cause seizures in flies, mice, and humans

Hirotaka Tao, J. Robert Manak, Levi Sowers, Xue Mei, Hiroshi Kiyonari, Takaya Abe, Nader S. Dahdaleh, Tian Yang, Shu Wu, Shan Chen, Mark H. Fox, Christina Gurnett, Thomas Montine, Thomas Bird, Lisa G. Shaffer, Jill A. Rosenfeld, Juliann McConnell, Suneeta Madan-Khetarpal, Elizabeth Berry-Kravis, Hilary GriesbachRussell P. Saneto, Matthew P. Scott, Dragana Antic, Jordan Reed, Riley Boland, Salleh N. Ehaideb, Hatem El-Shanti, Vinit B. Mahajan, Polly J. Ferguson, Jeffrey D. Axelrod, Anna Elina Lehesjoki, Bernd Fritzsch, Diane C. Slusarski, John Wemmie, Naoto Ueno*, Alexander G. Bassuk

*Corresponding author for this work

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

Original languageEnglish (US)
Pages (from-to)138-149
Number of pages12
JournalAmerican journal of human genetics
Volume88
Issue number2
DOIs
StatePublished - Feb 11 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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