Segregation analysis of juvenile myoclonic epilepsy

Greenberg, David A.; Delgado‐Escueta, Antonio V.; Maldonado, Héctor; Widelitz, Heidi; Rao, D. C.; Borecki, Ingrid B.

doi:10.1002/gepi.1370050204

Cited by 45 publications

(22 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our group originally reported strong linkage of a JME-related gene locus at 6p21, the region containing BRD2. 5 Association analysis pointed to the BRD2 gene as the best-supported candidate. [6][7][8] The JME-6p21 linkage was confirmed multiple times.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Few IGE genes have been identified, and those mostly through linkage scans chosen through specific phenotypes. Of those genes only BRD2 , which is not a channel gene, has been both linked and associated in multiple studies with a particular IGE, JME [5], [6], [7], [8], [9], [10], [11], [12]. The statistical and population evidence supports BRD2 as strongly influencing susceptibility to JME in particular and, potentially, a wider range of IGE syndromes/seizures, including photosensitivity [13], [14] and epilepsy-related electroencephalography (EEG) traits [6], [8].…”

Section: Introductionmentioning

confidence: 99%

GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

et al. 2011

Self Cite

View full text Add to dashboard Cite

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/− mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/− males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/− female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/− vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/− mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/− mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.

show abstract

“…Although IGE is mostly genetic in origin (Greenberg et al 1992), few IGE genes have been identified. Among those genes, BRD2 has been repeatedly both linked and associated with JME (Cavalleri et al 2007;Durner et al 1991;Greenberg et al 1988aGreenberg et al ,1988bGreenberg et al , 2000Pal et al 2003;Sander et al 1995;Weissbecker et al 1991), specifically in Caucasian populations (Greenberg et al 2000;Sander et al 1997).…”

mentioning

confidence: 99%

Sex‐specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy

Chachua

Goletiani

Maglakelidze

et al. 2014

Genes Brain and Behavior

View full text Add to dashboard Cite

Idiopathic generalized epilepsy represents about 30–35% of all epilepsies in humans. The bromodomain BRD2 gene has been repeatedly associated with the subsyndrome of juvenile myoclonic epilepsy. Our previous work determined that mice haploinsufficient in Brd2 (Brd2+/−) have increased susceptibility to provoked seizures, develop spontaneous seizures and have significantly decreased GABA markers in the direct basal ganglia pathway as well as in the neocortex and superior colliculus. Here we tested male and female Brd2+/− and wild type littermate mice in a battery of behavioral tests (open field, tube dominance test, elevated plus maze, Morris water maze and Barnes maze) to identify whether Brd2 haploinsufficiency is associated with the human behavioral patterns, so-called juvenile myoclonic epilepsy personality. Brd2+/− females but not males consistently displayed decreased anxiety. Further, we found a highly significant dominance trait (aggression) in the Brd2+/− mice compared to the wild type, more pronounced in females. Brd2+/− mice of either sex did not differ from wild type mice in spatial learning and memory tests. Compared to wild type littermates, we found decreased numbers GABA neurons in the basolateral amygdala, which is consistent with the increase in aggressive behavior. Our results indicate that Brd2+/− haploinsufficient mice show no cognitive impairment but have behavioral traits similar to those found in patients with juvenile myoclonic epilepsy (recklessness, aggression). This suggests that either the BRD2 gene is directly responsible for influencing many traits of juvenile myoclonic epilepsy or it controls upstream regulators of individual phenotypes.

show abstract

Segregation analysis of juvenile myoclonic epilepsy

Cited by 45 publications

References 5 publications

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians

GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

Sex‐specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy

Contact Info

Product

Resources

About