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Two genes, <jats:italic>LGI1<\/jats:italic> and <jats:italic>RELN<\/jats:italic>, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome\u2010wide single\u2010nucleotide polymorphism\u2010array linkage analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified two ADLTE\u2010causing variants in the <jats:italic>MICAL\u20101<\/jats:italic> gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C\u2010terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell\u2010based assays, both variants significantly increased MICAL\u20101 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F\u2010actin dynamics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>MICAL\u20101 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which <jats:italic>MICAL\u20101<\/jats:italic> pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483\u2013493<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25167","type":"journal-article","created":{"date-parts":[[2018,2,2]],"date-time":"2018-02-02T22:58:55Z","timestamp":1517612335000},"page":"483-493","source":"Crossref","is-referenced-by-count":42,"title":["Mutations in <i>MICAL\u20101<\/i>cause autosomal\u2010dominant lateral temporal epilepsy"],"prefix":"10.1002","volume":"83","author":[{"given":"Emanuela","family":"Dazzo","sequence":"first","affiliation":[{"name":"CNR\u2013Neuroscience Institute Section of Padua Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kati","family":"Rehberg","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Brain Center Rudolf Magnus UMC Utrecht, Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Michelucci","sequence":"additional","affiliation":[{"name":"IRCCS\u2013Institute of Neurological Sciences of Bologna, Unit of Neurology, Bellaria Hospital Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Passarelli","sequence":"additional","affiliation":[{"name":"Division of Neurology Infermi Hospital Faenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementina","family":"Boniver","sequence":"additional","affiliation":[{"name":"Clinical Neurophysiology, Department of Pediatrics University of Padua Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Vianello Dri","sequence":"additional","affiliation":[{"name":"APSS Trento, Mental Health Department Child and Adolescent Neuropsichiatry 1 Trento Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-1476","authenticated-orcid":false,"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, \u201cG. 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