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A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome |
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| Authors: | Bassuk Alexander G Wallace Robyn H Buhr Aimee Buller Andrew R Afawi Zaid Shimojo Masahito Miyata Shingo Chen Shan Gonzalez-Alegre Pedro Griesbach Hilary L Wu Shu Nashelsky Marcus Vladar Eszter K Antic Dragana Ferguson Polly J Cirak Sebahattin Voit Thomas Scott Matthew P Axelrod Jeffrey D Gurnett Christina Daoud Azhar S Kivity Sara Neufeld Miriam Y Mazarib Aziz Straussberg Rachel Walid Simri Korczyn Amos D Slusarski Diane C Berkovic Samuel F El-Shanti Hatem I |
| Affiliation: | 1 Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA 2 Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA 3 Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA 4 Department of Neurology, University of Iowa, Iowa City, IA 52242, USA 5 Department of Biology, University of Iowa, Iowa City, IA 52242, USA 6 Department of Pathology, University of Iowa, Iowa City, IA 52242, USA 7 Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia 8 Department of Neurology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel 9 Department of Molecular and Cellular Biochemistry, University of Kentucky, Louisville, KY 40536, USA 10 Department of Anatomy &; Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan 11 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA 12 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA 13 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA 14 Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA 15 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA 16 Universitätskinderklinik Essen, Abteilung für Allgemeine Pädiatrie mit Schwerpunkt Neuropädiatrie, 45122 Essen, Germany 17 Institut de Myologie Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France 18 Department of Neurology, Division Pediatric Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA 19 Department of Pediatrics, Jordan University of Science and Technology, Irbid 22110, Jordan 20 Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah 49202, Israel 21 Department of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikvah 49202, Israel 22 Kupat Holim Clalit, Nazareth 16000, Israel 23 Department of Neurology, Western Galilee Hospital, Nahariya 22100, Israel 24 Sieratzki Chair of Neurology, Tel Aviv University, Ramat Aviv 69978, Israel 25 Epilepsy Research Centre and Department of Medicine, University of Melbourne (Austin Health), Heidelberg West, Victoria 3161, Australia 26 Shafallah Medical Genetics Center, Doha, Qatar |
| Abstract: | Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy. |
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