Centrotemporal Sharp Wave EEG Trait in Rolandic Epilepsy Maps to Elongator Protein Complex 4 (ELP4)

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2009 Jan 29

PMID 19172991

Citations 67

Authors

Lisa J Strug

Tara Clarke

Theodore Chiang

Minchen Chien

Zeynep Baskurt

Weili Li

Ruslan Dorfman

Bhavna Bali

Elaine Wirrell

Steven L Kugler

David E Mandelbaum

Steven M Wolf

Patricia McGoldrick

Huntley Hardison

Edward J Novotny

Jingyue Ju

David A Greenberg

James J Russo

Deb K Pal

Affiliations

Soon will be listed here.

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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References

Hodge S, Abreu P, Greenberg D . Magnitude of type I error when single-locus linkage analysis is maximized over models: a simulation study. Am J Hum Genet. 1997; 60(1):217-27. PMC: 1712558. View

Anderson S, COLI R, Daly I, Kichula E, Rork M, Volpi S . Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet. 2001; 68(3):753-8. PMC: 1274486. DOI: 10.1086/318808. View

Abreu P, Hodge S, Greenberg D . Quantification of type I error probabilities for heterogeneity LOD scores. Genet Epidemiol. 2002; 22(2):156-69. DOI: 10.1002/gepi.0155. View

Daw E, Thompson E, Wijsman E . Bias in multipoint linkage analysis arising from map misspecification. Genet Epidemiol. 2000; 19(4):366-80. DOI: 10.1002/1098-2272(200012)19:4<366::AID-GEPI8>3.0.CO;2-F. View

Mezey E, Parmalee A, Szalayova I, Gill S, Cuajungco M, Leyne M . Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia?. Brain Res. 2003; 983(1-2):209-14. DOI: 10.1016/s0006-8993(03)03090-7. View

Roll P, Rudolf G, Pereira S, Royer B, Scheffer I, Massacrier A . SRPX2 mutations in disorders of language cortex and cognition. Hum Mol Genet. 2006; 15(7):1195-207. DOI: 10.1093/hmg/ddl035. View

Echenne B, Cheminal R, Rivier F, Negre C, Touchon J, Billiard M . Epileptic electroencephalographic abnormalities and developmental dysphasias: a study of 32 patients. Brain Dev. 1992; 14(4):216-25. DOI: 10.1016/s0387-7604(12)80233-6. View

Esberg A, Huang B, Johansson M, Bystrom A . Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis. Mol Cell. 2006; 24(1):139-48. DOI: 10.1016/j.molcel.2006.07.031. View

Kruglyak L, Daly M, Lander E . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996; 58(6):1347-63. PMC: 1915045. View

10.

HEIJBEL J, Blom S, Rasmuson M . Benign epilepsy of childhood with centrotemporal EEG foci: a genetic study. Epilepsia. 1975; 16(2):285-93. DOI: 10.1111/j.1528-1157.1975.tb06059.x. View

11.

Holtmann M, Becker K, Kentner-Figura B, Schmidt M . Increased frequency of rolandic spikes in ADHD children. Epilepsia. 2003; 44(9):1241-4. DOI: 10.1046/j.1528-1157.2003.13403.x. View

12.

Eeg-Olofsson O, Petersen I, SELLDEN U . The development of the electroencephalogram in normal children from the age of 1 through 15 years. Paroxysmal activity. Neuropadiatrie. 1971; 2(4):375-404. DOI: 10.1055/s-0028-1091791. View

13.

Niedermeyer E, MCKUSICK V, Brunt P, MAHLOUDJI M . The EEG in familial dysautonomia (Riley-Day syndrome). Electroencephalogr Clin Neurophysiol. 1967; 22(5):473-5. DOI: 10.1016/0013-4694(67)90176-9. View

14.

Boxerman J, Hawash K, Bali B, Clarke T, Rogg J, Pal D . Is Rolandic epilepsy associated with abnormal findings on cranial MRI?. Epilepsy Res. 2007; 75(2-3):180-5. PMC: 2001310. DOI: 10.1016/j.eplepsyres.2007.06.001. View

15.

Strug L, Hodge S . An alternative foundation for the planning and evaluation of linkage analysis. I. Decoupling "error probabilities" from "measures of evidence". Hum Hered. 2006; 61(3):166-88. DOI: 10.1159/000094709. View

16.

Krogan N, Greenblatt J . Characterization of a six-subunit holo-elongator complex required for the regulated expression of a group of genes in Saccharomyces cerevisiae. Mol Cell Biol. 2001; 21(23):8203-12. PMC: 99985. DOI: 10.1128/MCB.21.23.8203-8212.2001. View

17.

Guerrini R, Bonanni P, Nardocci N, Parmeggiani L, Piccirilli M, De Fusco M . Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2. Ann Neurol. 1999; 45(3):344-52. DOI: 10.1002/1531-8249(199903)45:3<344::aid-ana10>3.0.co;2-9. View

18.

Shinnar S, ODell C, Berg A . Distribution of epilepsy syndromes in a cohort of children prospectively monitored from the time of their first unprovoked seizure. Epilepsia. 1999; 40(10):1378-83. DOI: 10.1111/j.1528-1157.1999.tb02008.x. View

19.

Kong A, Gudbjartsson D, Sainz J, Jonsdottir G, Gudjonsson S, Richardsson B . A high-resolution recombination map of the human genome. Nat Genet. 2002; 31(3):241-7. DOI: 10.1038/ng917. View

20.

Kugler S, Bali B, Lieberman P, Strug L, Gagnon B, Murphy P . An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorder. Epilepsia. 2008; 49(6):1086-90. PMC: 2435390. DOI: 10.1111/j.1528-1167.2007.01517.x. View