Abstract
Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.
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Acknowledgements
We thank the families participating in the IRELAND study (http://www.rolandic.com); Irina Gurvich PhD, Regina Santella PhD, Fengli Zhang MD, Frances Rhoads MD, Jerry Boxerman MD PhD, Jeffrey Rogg MD, Lewis Kull MS, Geoffrey Tremont PhD, Janessa Carvalho BS, Suzanne Foster BS, George Cholankeril, Doe West PhD, Kieran Hartsough BS, Lynne Capuano, Somaria Persaud; and the members of the IRELAND consortium: Cigdem Akman MD, William D Brown MD, Murray Engel MD, John Gaitanis MD, Frank Gilliam MD, Karameh Hawash MD, Huntley Hardison MD, Geoffrey Heyer MD, Steven L Kugler MD, Linda Leary MD, David E Mandelbaum MD PhD, Patricia McGoldrick RN, Edward Novotny MD, Steven M Wolf MD and Maria Younes MD. This study was supported by members of the Partnership for Pediatric Epilepsy Research, which includes the American Epilepsy Society, the Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures (faces), Neurotherapy Ventures Charitable Research Fund and Parents Against Childhood Epilepsy (PACE) (DKP); the Epilepsy Foundation through the generous support of the Charles L Shor Foundation for Epilepsy Research Inc. (DKP); People Against Childhood Epilepsy (PACE) (DKP), National Institutes of Health grants NS047530 (DKP) and HG00-4314 (LJS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Neurological Disorders And Stroke, the National Institutes of Health or any other sponsor. We acknowledge Professor Hermann Doose's intellectual contribution to the nosology of focal sharp wave-associated phenotypes in children. We thank Dr Susan E Hodge for critical reading of the paper; Dr Andreas Kottman and Dr Livio Pellizzoni for helpful discussions.
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Mendelian variants of RE are listed in Online Inheritance in Man http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim. The Haploview application can be downloaded at http://www.broad.mit.edu/mpg/haploview. Information about marker location can be found at UniSTS at the NCBI website above and through the Ensembl genome browser at http://www.ensembl.org/Homo_sapiens/Info/Index. SNP frequencies were accessed at dbSNP: http://www.ncbi.nlm.nih.gov/projects/SNP.The ESE Finder program was used to assess alternative exon 10 of ELP4 and can be accessed at http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi?process=home. For bioinformatic analyses of ELP4 protein variants produced by alternative gene splicing we used PHI-BLAST, and accessed the following PANTHER and Bioinformatics websites: http://www.pantherdb.org and http://bioinformatics.weizmann.ac.il/blocks/blockmkr/www/make_blocks.html.
Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)
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Strug, L., Clarke, T., Chiang, T. et al. Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4). Eur J Hum Genet 17, 1171–1181 (2009). https://doi.org/10.1038/ejhg.2008.267
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DOI: https://doi.org/10.1038/ejhg.2008.267
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