title: Mutations in prickle orthologs cause seizures in flies, mice, and humans.
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.
authors.affiliation: Division of Morphogenesis, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tao
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
authors.forename: Levi
authors.initials: L
authors.lastname: Sowers
authors.forename: Xue
authors.initials: X
authors.lastname: Mei
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Nader S
authors.initials: NS
authors.lastname: Dahdaleh
authors.forename: Tian
authors.initials: T
authors.lastname: Yang
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.forename: Mark H
authors.initials: MH
authors.lastname: Fox
authors.forename: Christina
authors.initials: C
authors.lastname: Gurnett
authors.forename: Thomas
authors.initials: T
authors.lastname: Montine
authors.forename: Thomas
authors.initials: T
authors.lastname: Bird
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Juliann
authors.initials: J
authors.lastname: McConnell
authors.forename: Suneeta
authors.initials: S
authors.lastname: Madan-Khetarpal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Hilary
authors.initials: H
authors.lastname: Griesbach
authors.forename: Russell P
authors.initials: RP
authors.lastname: Saneto
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Scott
authors.forename: Dragana
authors.initials: D
authors.lastname: Antic
authors.forename: Jordan
authors.initials: J
authors.lastname: Reed
authors.forename: Riley
authors.initials: R
authors.lastname: Boland
authors.forename: Salleh N
authors.initials: SN
authors.lastname: Ehaideb
authors.forename: Hatem
authors.initials: H
authors.lastname: El-Shanti
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Axelrod
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
authors.forename: Diane C
authors.initials: DC
authors.lastname: Slusarski
authors.forename: John
authors.initials: J
authors.lastname: Wemmie
authors.forename: Naoto
authors.initials: N
authors.lastname: Ueno
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004831:Epilepsies, Myoclonic / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000209:etiology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D060588:LIM Domain Proteins; D009419:Nerve Tissue Proteins; C515173:PRICKLE1 protein, human; C524253:Prickle1 protein, mouse; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; C121600:pk protein, Drosophila; D002118:Calcium