{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:07:26Z","timestamp":1790737646612,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T00:00:00Z","timestamp":1522627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007520","name":"Nationwide Children's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007520","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,5]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>Juvenile myoclonic epilepsy (JME<\/jats:styled-content>) is a common adolescent\u2010onset genetic generalized epilepsy (GGE<\/jats:styled-content>) syndrome. Multiple linkage and association studies have found that BRD<\/jats:styled-content>2<\/jats:italic> influences the expression of JME<\/jats:styled-content>. The BRD2<\/jats:styled-content>\u2010<\/jats:italic>JME<\/jats:styled-content> connection is further corroborated by our murine model; Brd2<\/jats:italic> haploinsufficiency produces characteristics that typify the clinical hallmarks of JME<\/jats:styled-content>. Neither we, nor several large\u2010scale studies of JME<\/jats:styled-content>, found JME<\/jats:styled-content>\u2010related BRD<\/jats:styled-content>2<\/jats:italic> coding mutations. Therefore, we investigated noncoding BRD<\/jats:styled-content>2<\/jats:italic> regions, seeking the origin of BRD<\/jats:styled-content>2<\/jats:italic>'s JME<\/jats:styled-content> influence. BRD<\/jats:styled-content>2's<\/jats:italic> promoter harbors a JME<\/jats:styled-content>\u2010associated single nucleotide polymorphism (rs3918149) and a CpG (C\u2010phosphate\u2010G dinucleotides) island (CpG76), making it a potential \u201chotspot\u201d for JME<\/jats:styled-content>\u2010associated epigenetic variants. Methylating promoter CpG sites causes gene silencing, often resulting in reduced gene expression. We tested for differences in DNA<\/jats:styled-content> methylation at CpG76 in 3 different subgroups: (1) JME<\/jats:styled-content> patients versus their unaffected family members, (2) JME<\/jats:styled-content> versus patients with other forms of GGE<\/jats:styled-content>, and (3) Caucasian versus non\u2010Caucasian JME<\/jats:styled-content> patients.<\/jats:p><\/jats:sec>Methods<\/jats:title>We used DNA<\/jats:styled-content> pyrosequencing to analyze the methylation status of 10 BRD<\/jats:styled-content>2<\/jats:italic> promoter CpG sites in lymphoblastoid cells from JME<\/jats:styled-content> patients of Caucasian and non\u2010Caucasian origin, unaffected family members, and also non\u2010JME GGE<\/jats:styled-content> patients. We also measured global methylation levels and DNA<\/jats:styled-content> methyl transferase 1 (DNMT<\/jats:styled-content>1) transcript expression in JME<\/jats:styled-content> families by standard methods.<\/jats:p><\/jats:sec>Results<\/jats:title>CpG76 is highly methylated in JME<\/jats:styled-content> patients compared to unaffected family members. In families with non\u2010JME GGE<\/jats:styled-content>, we found no relationship between promoter methylation and epilepsy. In non\u2010Caucasian JME<\/jats:styled-content> families, promoter methylation was mostly not associated with epilepsy. This makes the BRD<\/jats:styled-content>2<\/jats:italic> promoter a JME<\/jats:styled-content>\u2010specific, ethnicity\u2010specific, differentially methylated region. Global methylation was constant across groups.<\/jats:p><\/jats:sec>Significance<\/jats:title>BRD<\/jats:styled-content>2<\/jats:italic> promoter methylation in JME<\/jats:styled-content>, and the lack of methylation in unaffected relatives, in non\u2010JME GGE<\/jats:styled-content> patients, and in non\u2010Caucasian JME<\/jats:styled-content>, demonstrate that methylation specificity is a possible seizure susceptibility motif in JME<\/jats:styled-content> risk and suggests JME<\/jats:styled-content> therapeutics targeting BRD<\/jats:styled-content>2<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14058","type":"journal-article","created":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T16:25:32Z","timestamp":1522686332000},"page":"1011-1019","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["DNA<\/scp> methylation of the BRD<\/scp>2<\/i> promoter is associated with juvenile myoclonic epilepsy in Caucasians"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6341-089X","authenticated-orcid":false,"given":"Shilpa","family":"Pathak","sequence":"first","affiliation":[{"name":"Battelle Center for Mathematical Medicine Research Institute Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Miller","sequence":"additional","affiliation":[{"name":"Battelle Center for Mathematical Medicine Research Institute Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Morris","sequence":"additional","affiliation":[{"name":"Battelle Center for Mathematical Medicine Research Institute Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C. 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