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Here we describe three mouse lines on the C57BL\/6J background with novel, overlapping mutations in the <jats:italic>Scn8a<\/jats:italic> DIIS4 voltage sensor: an in\u2010frame 9 bp deletion (<jats:italic>\u03949<\/jats:italic>), an in\u2010frame 3 bp insertion (<jats:italic>\u22073<\/jats:italic>) and a 35\u2009bp deletion that results in a frameshift and the generation of a null allele (<jats:italic>\u039435<\/jats:italic>). <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u03949\/+<\/jats:italic><\/jats:sup> and <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u22073\/+<\/jats:italic><\/jats:sup> heterozygous mutants display subtle motor deficits, reduced acoustic startle response, and are resistant to induced seizures, suggesting that these mutations reduce activity of the <jats:italic>Scn8a<\/jats:italic> channel protein, Na<jats:sub>v<\/jats:sub>1.6. Heterozygous <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u039435\/+<\/jats:italic><\/jats:sup> mutants show no alterations in motor function or acoustic startle response, but are resistant to induced seizures. Homozygous mutants from each line exhibit premature lethality and severe motor impairments, ranging from uncoordinated gait with tremor (<jats:italic>\u03949<\/jats:italic> and <jats:italic>\u22073<\/jats:italic>) to loss of hindlimb control (<jats:italic>\u039435<\/jats:italic>). <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u03949\/\u03949<\/jats:italic><\/jats:sup> and <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u22073\/\u22073<\/jats:italic><\/jats:sup> homozygous mutants also exhibit impaired nerve conduction velocity, while normal nerve conduction was observed in <jats:italic>Scn8a<\/jats:italic><jats:sup>\n<jats:italic>\u039435\/\u039435<\/jats:italic><\/jats:sup> homozygous mice. Our results suggest that hypomorphic mutations that reduce Na<jats:sub>v<\/jats:sub>1.6 activity will likely result in different clinical phenotypes compared to null alleles. These three mouse lines represent a valuable opportunity to examine the phenotypic impacts of hypomorphic and null <jats:italic>Scn8a<\/jats:italic> mutations without the confound of strain\u2010specific differences.<\/jats:p>","DOI":"10.1111\/gbb.12612","type":"journal-article","created":{"date-parts":[[2019,10,12]],"date-time":"2019-10-12T00:19:50Z","timestamp":1570839590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mutations in the <i>Scn8a<\/i> DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Na<sub>v<\/sub>1.6 sodium channels"],"prefix":"10.1111","volume":"19","author":[{"given":"George Andrew S.","family":"Inglis","sequence":"first","affiliation":[{"name":"Department of Human Genetics Emory University  Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Human 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