{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:14Z","timestamp":1782281054099,"version":"3.54.5"},"posted":{"date-parts":[[2026,4,26]]},"group-title":"Neuroscience","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health National Institute of Neurological Disorders and Stroke","award":["F31NS143238"],"award-info":[{"award-number":["F31NS143238"]}]},{"name":"Robert J. and Nancy D. Carney Institute for Brain Science"},{"name":"HOPE for Annabel"},{"name":"Hope4Livi"},{"name":"Cure AHC"},{"name":"The Alternating Hemiplegia of Childhood Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Dominant missense mutations in ATP1A3, encoding a Na\n                  <jats:sup>+<\/jats:sup>\n                  , K\n                  <jats:sup>+<\/jats:sup>\n                  ATPase \u03b1-3 subunit, can cause Alternating Hemiplegia of Childhood (AHC), but how these mutations lead to AHC remains unclear. Here, we establish the first\n                  <jats:italic>C. elegans<\/jats:italic>\n                  AHC models by introducing AHC-causing ATP1A3 patient mutations (D801N, E815K, L839P, and G947R) into the orthologous gene,\n                  <jats:italic>eat-6,<\/jats:italic>\n                  using CRISPR\/Cas9. Homozygous\n                  <jats:italic>C. elegans<\/jats:italic>\n                  AHC model animals have recessive developmental defects. Heterozygous AHC model animals have dominant defects in neuromuscular junction (NMJ) function that are inconsistent with haploinsufficiency and dominant sleep or arousal defects. Previous work in a\n                  <jats:italic>Drosophila<\/jats:italic>\n                  G755S AHC model found that loss of a K\u207a-dependent, Na\u207a\/Ca\u00b2\u207a exchanger exacerbated neuronal defects. We introduced a loss-of-function allele of the orthologous\n                  <jats:italic>C. elegans<\/jats:italic>\n                  gene,\n                  <jats:italic>ncx-4<\/jats:italic>\n                  , into\n                  <jats:italic>C. elegans<\/jats:italic>\n                  AHC models; loss of\n                  <jats:italic>ncx-4<\/jats:italic>\n                  function did not consistently alter\n                  <jats:italic>C. elegans<\/jats:italic>\n                  AHC model defects across alleles. Our results establish novel\n                  <jats:italic>C. elegans<\/jats:italic>\n                  models of AHC with robust phenotypes, demonstrate that AHC mutations disrupt NMJ function, and provide proof-of-concept for discovering cross-species modifiers of AHC-related phenotypes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary Statement<\/jats:title>\n                  <jats:p>\n                    We report the first\n                    <jats:italic>C. elegans<\/jats:italic>\n                    models of Alternating Hemiplegia of Childhood. D801N, E815K, L839P, and G947R AHC model animals have recessive development defects and dominant neuromuscular defects.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.22.720250","type":"posted-content","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:30:11Z","timestamp":1777264211000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>C. elegans<\/i>\n                  models of Alternating Hemiplegia of Childhood have dominant neuromuscular junction defects"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-1796","authenticated-orcid":false,"given":"Diana A.","family":"Wall","sequence":"first","affiliation":[{"name":"Brown University Department of Molecular Biology, Cell Biology, and Biochemistry"},{"name":"Robert J. and Nancy D. 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