TY - JOUR
T1 - Mutations in prickle orthologs cause seizures in flies, mice, and humans
AU - Tao, Hirotaka
AU - Manak, J. Robert
AU - Sowers, Levi
AU - Mei, Xue
AU - Kiyonari, Hiroshi
AU - Abe, Takaya
AU - Dahdaleh, Nader S.
AU - Yang, Tian
AU - Wu, Shu
AU - Chen, Shan
AU - Fox, Mark H.
AU - Gurnett, Christina
AU - Montine, Thomas
AU - Bird, Thomas
AU - Shaffer, Lisa G.
AU - Rosenfeld, Jill A.
AU - McConnell, Juliann
AU - Madan-Khetarpal, Suneeta
AU - Berry-Kravis, Elizabeth
AU - Griesbach, Hilary
AU - Saneto, Russell P.
AU - Scott, Matthew P.
AU - Antic, Dragana
AU - Reed, Jordan
AU - Boland, Riley
AU - Ehaideb, Salleh N.
AU - El-Shanti, Hatem
AU - Mahajan, Vinit B.
AU - Ferguson, Polly J.
AU - Axelrod, Jeffrey D.
AU - Lehesjoki, Anna Elina
AU - Fritzsch, Bernd
AU - Slusarski, Diane C.
AU - Wemmie, John
AU - Ueno, Naoto
AU - Bassuk, Alexander G.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01 NS064159 and 3R01NS064159-02S1 (to A.G.B.), R01 GM059823 (to J.D.A.), RO1 CA112369 (to D.C.S.), and P50 AG05136 (to T.M.), by 1R21NS058309-01A1 (to J.W.), by a VA Merit Review Award (to J.W.), and by a grant from the Howard Hughes Medical Institute (to M.S.). We thank Jeff Murray, Jeff Neul, Val Sheffield, Bev Davidson, Zoha Kibar, Heather Mefford, and Sam Berkovic for their thoughtful reviews. We thank Jeff Murray for access to the CEPH-HGD samples and Taqman assay. L.G.S. and J.A.R. are employed by Signature Genomics Laboratories.
PY - 2011/2/11
Y1 - 2011/2/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79851516501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79851516501&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2010.12.012
DO - 10.1016/j.ajhg.2010.12.012
M3 - Article
C2 - 21276947
AN - SCOPUS:79851516501
VL - 88
SP - 138
EP - 149
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -