Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans

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• 作者：Hirotaka Tao¹ ; ²⁴ ; J. Robert Manak² ; ²⁴ ; Levi Sowers³ ; ²⁴ ; Xue Mei² ; Hiroshi Kiyonari⁴ ; Takaya Abe⁴ ; Nader S. Dahdaleh⁵ ; Tian Yang² ; Shu Wu⁶ ; Shan Chen⁶ ; Mark H. Fox⁶ ; Christina Gurnett⁷ ; Thomas Montine⁸ ; Thomas Bird⁹ ; Lisa G. Shaffer¹⁰ ; Jill A. Rosenfeld¹⁰ ; Juliann McConnell¹¹ ; Suneeta Madan-Khetarpal¹¹ ; Elizabeth Berry-Kravis¹² ; Hilary Griesbach² ; Russell P. Saneto¹³ ; Matthew P. Scott¹⁴ ; Dragana Antic¹⁴ ; ¹⁵ ; Jordan Reed² ; Riley Boland² ; Salleh N. Ehaideb² ; Hatem El-Shanti¹⁶ ; ¹⁷ ; Vinit B. Mahajan¹⁸ ; Polly J. Ferguson⁶ ; Jeffrey D. Axelrod¹⁵ ; Anna-Elina Lehesjoki¹⁹ ; Bernd Fritzsch² ; Diane C. Slusarski² ; John Wemmie²⁰ ; ²¹ ; Naoto Ueno¹ ; ²² ; ^{nueno@nibb.ac.jp} ; Alexander G. Bassuk²³ ; ^{alexander-bassuk@uiowa.edu}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 February 2011
• 年：2011
• 卷：88
• 期：2
• 页码：138-149
• 全文大小：1014 K

文摘

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.