Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4)

被引：150
作者：
Strug, Lisa J. [2 ,3 ]
Clarke, Tara
Chiang, Theodore [2 ]
Chien, Minchen [4 ,5 ]
Baskurt, Zeynep [2 ]
Li, Weili [2 ]
Dorfman, Ruslan [6 ]
Bali, Bhavna
Wirrell, Elaine [7 ]
Kugler, Steven L. [8 ,9 ]
Mandelbaum, David E. [10 ,11 ]
Wolf, Steven M. [12 ]
McGoldrick, Patricia [12 ]
Hardison, Huntley [13 ]
Novotny, Edward J. [14 ]
Ju, Jingyue [4 ,5 ]
Greenberg, David A. [1 ,15 ]
Russo, James J. [4 ,5 ]
Pal, Deb K. [1 ,16 ]
机构：
[1] Columbia Univ, Med Ctr, Mailman Sch Publ Hlth, Dept Epidemiol,Div Stat Genet, New York, NY 10032 USA
[2] Hosp Sick Children, Child Hlth Evaluat Sci, Toronto, ON M5G 1X8, Canada
[3] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada
[4] Judith P Sulzberger MD Columbia Genome Ctr, New York, NY USA
[5] Columbia Univ, Med Ctr, Dept Chem Engn, New York, NY 10032 USA
[6] Hosp Sick Children, Program Genet & Genom Biol, Toronto, ON M5G 1X8, Canada
[7] Univ Calgary, Alberta Childrens Hosp, Div Pediat Neurol, Calgary, AB, Canada
[8] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA
[9] Univ Penn, Sch Med, Philadelphia, PA 19104 USA
[10] Brown Univ, Hasbro Childrens Hosp, Dept Clin Neurosci, Providence, RI 02912 USA
[11] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA
[12] Beth Israel Deaconess Med Ctr, Epilepsy Monitoring Unit, New York, NY 10003 USA
[13] St Christophers Hosp Children, Div Pediat Neurol, Philadelphia, PA 19133 USA
[14] Yale Univ, Med Ctr, Dept Pediat, New Haven, CT USA
[15] New York State Psychiat Inst & Hosp, New York, NY 10032 USA
[16] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY 10032 USA
来源：
EUROPEAN JOURNAL OF HUMAN GENETICS | 2009年 / 17卷 / 09期
基金：
美国国家卫生研究院;
关键词：
linkage; neurodevelopmental traits; centrotemporal spikes; idiopathic partial epilepsy; association; LINKAGE ANALYSIS; ALTERNATIVE FOUNDATION; FAMILIAL DYSAUTONOMIA; BENIGN EPILEPSY; CHILDREN; EXPRESSION; RNA; TRANSCRIPTION; IMPAIRMENT; DISORDERS;
D O I：
10.1038/ejhg.2008.267
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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. European Journal of Human Genetics (2009) 17, 1171-1181; doi:10.1038/ejhg.2008.267; published online 28 January 2009
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页码：1171 / 1181
页数：11
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