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A recurrent de novo gain\u2010of\u2010function missense mutation in the\n                      <jats:italic>FHF1(FGF12)<\/jats:italic>\n                      gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the\n                      <jats:italic>FHF1<\/jats:italic>\n                      missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate\n                      <jats:italic>\n                        Fhf1\n                        <jats:sup>R52H<\/jats:sup>\n                        <jats:sup>\/F+<\/jats:sup>\n                      <\/jats:italic>\n                      mice. Spontaneous epileptiform events in\n                      <jats:italic>\n                        Fhf1\n                        <jats:sup>R52H<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\/+<\/jats:sup>\n                      mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure\u2010induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1B\n                      <jats:sub>R52H<\/jats:sub>\n                      protein was assayed by voltage\u2010clamp recordings of FHF\u2010deficient mouse cardiomyocytes infected with adenoviruses expressing wild\u2010type FHF1B or FHF1B\n                      <jats:sub>R52H<\/jats:sub>\n                      protein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All\n                      <jats:italic>\n                        Fhf1\n                        <jats:sup>R52H<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\/+<\/jats:sup>\n                      mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26\u00a0days of age. EEG recordings in 19\u201320\u2010day\u2010old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2\u201353\u00a0s after lethal seizure onset, heart rate abruptly declined from 572\u00a0\u00b1\u00a016\u00a0bpm to 108\u00a0\u00b1\u00a015\u00a0bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1B\n                      <jats:sub>R52H<\/jats:sub>\n                      in cardiomyocytes induced a 15\u2010mV depolarizing shift in voltage of steady\u2010state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in\n                      <jats:italic>\n                        Fhf1\n                        <jats:sup>R52H<\/jats:sup>\n                      <\/jats:italic>\n                      <jats:sup>\/+<\/jats:sup>\n                      mice prior to seizure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>Fhf1<\/jats:italic>\n                      missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both\n                      <jats:italic>Fhf1<\/jats:italic>\n                      (p.Arg52His) and\n                      <jats:italic>Scn8a<\/jats:italic>\n                      (p.Asn1768Asp) missense mutations enhance sodium channel Na\n                      <jats:sub>v<\/jats:sub>\n                      1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1\/Na\n                      <jats:sub>v<\/jats:sub>\n                      1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.16916","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T04:16:58Z","timestamp":1620879418000},"page":"1546-1558","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain\u2010of\u2010function\n                    <i>FHF1(FGF12)<\/i>\n                    missense mutation"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6094-7210","authenticated-orcid":false,"given":"Jana","family":"Vel\u00ed\u0161kov\u00e1","sequence":"first","affiliation":[{"name":"Department of Cell Biology &amp; Anatomy and Department of Neurology New York Medical College Valhalla New York USA"},{"name":"Department of Obstetrics and Gynecology New York Medical College Valhalla New York USA"},{"name":"Department of Neurology New York Medical College Valhalla New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4647-305X","authenticated-orcid":false,"given":"Christopher","family":"Marra","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Hunter College of City University of New York New York New York USA"},{"name":"Program in Biology Graduate Center of City University of New York New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Hunter College of City University of New York New York New York USA"},{"name":"Program in Biology Graduate Center of City University of New York New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Shekhar","sequence":"additional","affiliation":[{"name":"Leon H. Charney Division of Cardiology New York University School of Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Park","sequence":"additional","affiliation":[{"name":"Leon H. Charney Division of Cardiology New York University School of Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilisa","family":"Iatckova","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Hunter College of City University of New York New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Hunter College of City University of New York New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-8527","authenticated-orcid":false,"given":"Glenn I.","family":"Fishman","sequence":"additional","affiliation":[{"name":"Leon H. Charney Division of Cardiology New York University School of Medicine New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2805-349X","authenticated-orcid":false,"given":"Libor","family":"Vel\u00ed\u0161ek","sequence":"additional","affiliation":[{"name":"Department of Cell Biology &amp; Anatomy and Department of Neurology New York Medical College Valhalla New York USA"},{"name":"Department of Neurology New York Medical College Valhalla New York USA"},{"name":"Department of Pediatrics New York Medical College Valhalla New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-7645","authenticated-orcid":false,"given":"Mitchell","family":"Goldfarb","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Hunter College of City University of New York New York New York USA"},{"name":"Program in Biology Graduate Center of City University of New 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