Juvenile Myoclonic Epilepsy (JME) is a common epilepsy syndrome that starts in adolescence or young adulthood and requires lifelong treatment. BRD2 is a gene that, in some populations, is a causal factor in JME and in related electroencephalographic phenomena, which is demonstrated by replicated linkage and association studies. Based on family and population genetic analysis, it is currently the best candidate gene for a common epilepsy. This evidence is further strengthened by our studies of a Brd2 knockout mouse. The knockout data show that absence of BRD2 is incompatible with life. In heterozygote knockout mice (Brd2), the neural substrate is altered: there is a deficit of inhibitory neurons in two brain regions we have studied. Most compellingly, the heterozygotes show increased seizure susceptibility with a differential male/female pattern reminiscent of the pattern for JME in humans. We hypothesize that, in humans, mis- expression results in a slight insufficiency of BRD2 protein, leading to subtle changes in brain organization. Several lines of human imaging data report observing disruptions of neural substrate in JME patients, supporting the population genetic and mouse studies. We propose collaborative, multidisciplinary studies to determine the effect of altered BRD2 expression on brain substrate and function, and to identify the mechanisms by which such disturbances lead to brain hyperexcitability and seizures.
Our aims are: 1) To fully characterize changes to the neural substrate, behavior, seizure susceptibility, and electrophysiology caused by insufficiency of murine Brd2 protein in Brd2 mice. This includes using brain- slice experiments to study the behavior of neural circuits in Brd2 mice compared to wild type, as well as investigating the responses of individual neurons. 2) To identify the specific change(s) in the expression of the human BRD2 gene that lead to brain hyperexcitability. We will express human BRD2 alleles associated with JME in tissue culture, study changes in their transcription, splicing, and translation, and correlate those changes with specific polymorphisms. We will examine polymorphisms in the BRD2 promoters, 3'UTR and 5'UTR, and other gene regions. In particular, we identified a highly conserved, alternately-spiced exon located in intron 2. We hypothesize that CA-repeat polymorphisms, found in intron 2 and associated with JME, affect the balance of alternatively spliced forms. New preliminary experiments show that the composition of the inter-exon DNA alters the splicing characteristics of the alternate exon. We will insert varying sizes of CA-repeat polymorphisms at that locus to observe the effect on levels of alternatively spliced BRD2 transcripts, eventually studying the fate of both the normal and alternately spliced RNA.

Public Health Relevance

Project Narrative We propose to define the genetic, neuroanatomical, and circuitry mechanisms by which the gene BRD2 leads to susceptibility to Juvenile Myoclonic Epilepsy, a common epilepsy of adolescent onset and one that requires life-long medication to suppress seizures. The BRD2 gene, which we identified through studies of human epilepsy, has a profound effect on neural structure and circuitry. BRD2 is one of the few proven genes for a common epilepsy. This work could, at last, lead to understanding the basic cause and mechanism of an epilepsy that affects millions of Americans and places a difficult burden on the patient, their families, and the health care system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS061829-02S1
Application #
8109724
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$35,719
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Subaran, Ryan L; Odgerel, Zagaa; Swaminathan, Rajeswari et al. (2016) Novel variants in ZNF34 and other brain-expressed transcription factors are shared among early-onset MDD relatives. Am J Med Genet B Neuropsychiatr Genet 171B:333-41
Subaran, Ryan L; Conte, Juliette M; Stewart, William C L et al. (2015) Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia 56:188-94
Lipner, Ettie M; Tomer, Yaron; Noble, Janelle A et al. (2015) Linkage Analysis of Genomic Regions Contributing to the Expression of Type 1 Diabetes Microvascular Complications and Interaction with HLA. J Diabetes Res 2015:694107
Corso, Barbara; Greenberg, David A (2014) Using linkage analysis to detect gene-gene interaction by stratifying family data on known disease, or disease-associated, alleles. PLoS One 9:e93398
Greenberg, David A; Stewart, William L (2014) Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective on why progress on identifying genetic influences on common epilepsies has been so slow. Prog Brain Res 213:199-221
Chachua, T; Goletiani, C; Maglakelidze, G et al. (2014) Sex-specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy. Genes Brain Behav 13:702-12
Lipner, E M; Tomer, Y; Noble, J A et al. (2013) HLA class I and II alleles are associated with microvascular complications of type 1 diabetes. Hum Immunol 74:538-44
Greenberg, David A; Stewart, William C L (2012) How should we be searching for genes for common epilepsy? A critique and a prescription. Epilepsia 53 Suppl 4:72-80
Stewart, William C L; Subaran, Ryan L (2012) Obtaining accurate p values from a dense SNP linkage scan. Hum Hered 74:12-6
Shang, Enyuan; Cui, Qingping; Wang, Xiangyuan et al. (2011) The bromodomain-containing gene BRD2 is regulated at transcription, splicing, and translation levels. J Cell Biochem 112:2784-93

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