Mutations in prickle orthologs cause seizures in flies, mice, and humans期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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

Authors:	Tao Hirotaka Manak J 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 Bassuk Alexander G

Affiliation:	¹Division of Morphogenesis, National institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan;²Department of Biology, University of Iowa, Iowa City, Iowa 52242, USA;³Department of Pediatrics, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA;⁴Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-047, Japan;⁵Department of Neurosurgery, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA;⁶Department of Pediatrics, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA;⁷Department of Neurology, Washington University, St. Louis, MO 63310, USA;⁸Department of Pathology, University of Washington, Seattle, WA 98104, USA;⁹University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98104, USA;¹⁰Signature Genomic Laboratories, Spokane, WA 99202, USA;¹¹Children's Hospital of Pittsburgh UPMC, Medical Genetics, 4401 Penn Avenue, Pittsburgh, PA 15224, USA;¹²Departments of Pediatrics, Neurological Sciences and Biochemistry, Rush Medical Center, 1725 West Harrison St, Suite 718, Chicago, IL 60612, USA;¹³Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, WA 98105, USA;¹⁴Departments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA;¹⁵Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA;¹⁶Shafallah Medical Genetics Center, 69 Lusail St. West Bay Area, P.O. Box 33123, Doha 33123, Qatar;¹⁷Department of Pediatrics, the University of Iowa Carver College of Medicine, Iowa City, IA, USA 52242;¹⁸Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA;¹⁹Folkhalsan Institute of Genetics and Neuroscience Center, University of Helsinki, Helsinki 00014, Finland;²⁰Departments of Psychiatry and Neurosurgery, Neuroscience Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, IA City, IA 52242;²¹Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA;²²Department of Basic Biology, School of Life Science, Graduate University of Advanced Studies (SOKENDAI), 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan;²³Department of Pediatrics, The University of Iowa Carver College of Medicine, 25 S. Grand Avenue, 2044 Medical Lab Building, Iowa City, IA 52242, USA

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.

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