Journal article
A Homozygous Mutation in Human PRICKLE1 Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome
AG Bassuk, RH Wallace, A Buhr, AR Buller, Z Afawi, M Shimojo, S Miyata, S Chen, P Gonzalez-Alegre, HL Griesbach, S Wu, M Nashelsky, EK Vladar, D Antic, PJ Ferguson, S Cirak, T Voit, MP Scott, JD Axelrod, C Gurnett Show all
American Journal of Human Genetics | Published : 2008
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. PRI..
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Awarded by National Institutes of Health
Funding Acknowledgements
We thank the members of the families for their participation. We thank Chantal Allamargot and Kathy Walters for their assistance with immunostaining and confocal microscopy at the University of Iowa, and Kaye Suyama for her work with the antibodies at Stanford. A.G.B. is supported by NIH/NINDS grant K08NS48174. M.P.S. is an investigator of the Howard Hughes Medical Institute. D.C.S. and H.L.G. were Supported by NIH CA112369. M.S. was Supported by NIH/NCRR P20RR020171 and NIH MH067123. A.B. was supported by a grant from the Epilepsy Foundation. We thank Jeffrey Murray for access to the CEPH-HGD panel and for commentary on the manuscript. The authors have no disclosures and no conflicts of interest. A.G.B. wrote the manuscript, performed all immunohistochemical studies in HeLa cells and half of the tissue immunostaining, and oversaw all aspects of the resequencing, control genotyping, and coimmunoprecipitations. H.E. and A.D. clinically evaluated part of pedigree B. S.B. clinically evaluated all the pedigrees and integrated the clinical data, together with Z.A., S.K., A.K., M.N., S.W., A.Z., and R.S. H.E. and S.B. designed the mapping strategies. R.W., A.B., and S.C. performed the fine mapping, resequencing, and genotyping studies. A.B. compiled Table SI. S.C. compiled Table S2. A.R.B. performed the coimmunoprecipitations. RE and J.M.. assisted in the design and analysis of he genotyping assays. M.N. ascertained and prepared the specimens for human tissue staining. S.W. prepared the Prickle1 antibody at the University of Iowa. P.G. assisted in the development of the cell-culture experiments. D.C.S. oversaw all zebrafish injections and analyses performed by H.L.G. M.S. provided the myc-REST construct and guidance in cell transfections. S.M. provided a Mouse prickle1-GFP expression vector that was used in pilot studies in preparation for the use of a human Prickle1-EGFP construct. J.A., M.P.S., D.A., and E.K.V. produced the Prickle1 antibodies and performed the immunostaining at Stanford University.