Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy

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dc.citation.issue11
dc.citation.volumev. 378
dc.contributor.authorBailey, J. N.
dc.contributor.authorde Nijs, L.
dc.contributor.authorBai, D.
dc.contributor.authorSuzuki, T.
dc.contributor.authorMiyamoto, H.
dc.contributor.authorTanaka, M.
dc.contributor.authorPatterson, C.
dc.contributor.authorLin, Y. -C.
dc.contributor.authorMedina, M. T.
dc.contributor.authorAlonso, M. E.
dc.contributor.authorSerratosa, J. M.
dc.contributor.authorDuron, R. M.
dc.contributor.authorNguyen, V. H.
dc.contributor.authorWight, J. E.
dc.contributor.authorMartinez-Juarez, I. E.
dc.contributor.authorOchoa, A.
dc.contributor.authorJara-Prado, A.
dc.contributor.authorGuilhoto, Laura Maria de Figueiredo Ferreira [UNIFESP]
dc.contributor.authorMolina, Y.
dc.contributor.authorYacubian, Elza Márcia Targas [UNIFESP]
dc.contributor.authorLopez-Ruiz, M.
dc.contributor.authorInoue, Y.
dc.contributor.authorKaneko, S.
dc.contributor.authorHirose, S.
dc.contributor.authorOsawa, M.
dc.contributor.authorOguni, H.
dc.contributor.authorFujimoto, S.
dc.contributor.authorGrisar, T. M.
dc.contributor.authorStern, J. M.
dc.contributor.authorYamakawa, K.
dc.contributor.authorLakaye, B.
dc.contributor.authorDelgado-Escueta, A. V.
dc.coverageWaltham
dc.date.accessioned2020-07-20T16:31:15Z
dc.date.available2020-07-20T16:31:15Z
dc.date.issued2018
dc.description.abstractBACKGROUND In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase (ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS A variant, K305T (c.914A -> C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wildtype mice (P = 0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy.en
dc.description.affiliationUniv Calif Los Angeles, David Geffen Sch Med, Vet Affairs Greater Angeles Healthcare Syst, Neurol & Res Serv,Epilepsy Genet Genom Lab, Los Angeles, CA 90095 USA
dc.description.affiliationUniv Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
dc.description.affiliationUniv Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA
dc.description.affiliationChapman Univ, Irvine, CA USA
dc.description.affiliationUniv Liege, Grp Interdisciplinaire Genoproteom Appl Neurosci, Liege, Belgium
dc.description.affiliationRIKEN, Brain Sci Inst, Saitama, Japan
dc.description.affiliationShizuoka Inst Epilepsy & Neurol Disorders, Shizuoka, Japan
dc.description.affiliationHirosaki Univ, Grad Sch Med, Hirosaki, Aomori, Japan
dc.description.affiliationFukuoka Univ, Fukuoka, Japan
dc.description.affiliationTokyo Womens Med Univ, Tokyo, Japan
dc.description.affiliationNagoya City Univ, Nagoya, Aichi, Japan
dc.description.affiliationTsutsujigaoka Childrens Clin, Nagoya, Aichi, Japan
dc.description.affiliationNatl Autonomous Univ Honduras, Tegucigalpa, Honduras
dc.description.affiliationUniv Tecnol Ctr Amer, Tegucigalpa, Honduras
dc.description.affiliationNatl Inst Neurol & Neurosurg Manuel Velasco Suare, Mexico City, DF, Mexico
dc.description.affiliationGen Hosp Mexico, Mexico City, DF, Mexico
dc.description.affiliationUniv Fed Sao Paulo, Sao Paulo, SP, Brazil
dc.description.affiliationAutonomous Univ Madrid, Inst Invest Sanit, Fdn Jimenez Diaz, Madrid, Spain
dc.description.affiliationBiomed Res Network Ctr Rare Dis, Madrid, Spain
dc.description.affiliationUnifespUniv Fed Sao Paulo, Sao Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipNational Institutes of Health
dc.format.extent1018-1028
dc.identifierhttp://dx.doi.org/10.1056/NEJMoa1700175
dc.identifier.citationNew England Journal Of Medicine. Waltham, v. 378, n. 11, p. 1018-1028, 2018.
dc.identifier.doi10.1056/NEJMoa1700175
dc.identifier.issn0028-4793
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55814
dc.identifier.wosWOS:000427399000007
dc.language.isoeng
dc.publisherMassachusetts Medical Soc
dc.relation.ispartofNew England Journal Of Medicine
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleVariant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsyen
dc.typeinfo:eu-repo/semantics/article
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