Title | Mutations in prickle orthologs cause seizures in flies, mice, and humans. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Tao, Hirotaka, J Manak Robert, Sowers Levi, Mei Xue, Kiyonari Hiroshi, Abe Takaya, Dahdaleh Nader S., Yang Tian, Wu Shu, Chen Shan, Fox Mark H., Gurnett Christina, Montine Thomas, Bird Thomas, Shaffer Lisa G., Rosenfeld Jill A., McConnell Juliann, Madan-Khetarpal Suneeta, Berry-Kravis Elizabeth, Griesbach Hilary, Saneto Russell P., Scott Matthew P., Antic Dragana, Reed Jordan, Boland Riley, Ehaideb Salleh N., El-Shanti Hatem, Mahajan Vinit B., Ferguson Polly J., Axelrod Jeffrey D., Lehesjoki Anna-Elina, Fritzsch Bernd, Slusarski Diane C., Wemmie John, Ueno Naoto, and Bassuk Alexander G. |
Journal | American journal of human genetics |
Volume | 88 |
Issue | 2 |
Pagination | 138-49 |
Date Published | 2011 Feb 11 |
Keywords | Animals, Blotting, Western, Brain, Calcium, Carrier Proteins, DNA-Binding Proteins, Drosophila melanogaster, Drosophila Proteins, Embryo, Nonmammalian, Epilepsies, Myoclonic, Female, Heterozygote, Humans, Immunoenzyme Techniques, In Situ Hybridization, Male, Mice, Mice, Knockout, Mutation, Nerve Tissue Proteins, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Seizures, Tumor Suppressor Proteins, Zebrafish, Zebrafish Proteins |
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. |
Alternate Journal | Am. J. Hum. Genet. |