{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:50:58Z","timestamp":1788544258606,"version":"build-2803163510"},"reference-count":72,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T00:00:00Z","timestamp":1691712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2019804"],"award-info":[{"award-number":["2019804"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pathogenic variation in\n                    <jats:italic>HCN1<\/jats:italic>\n                    is now an established cause of epilepsy and intellectual disability. Variation in\n                    <jats:italic>HCN1<\/jats:italic>\n                    causes a spectrum of disease with a genotype\u2013phenotype relationship emerging. De novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation \u2018leak\u2019 that associates with severe developmental and epileptic encephalopathy (DEE). Genotype\u2013phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited.\n                    <jats:italic>HCN1<\/jats:italic>\n                    DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with human\n                    <jats:italic>HCN1<\/jats:italic>\n                    DEE patients. Data from these mouse models support the conclusion that anti\u2010seizure medications with sodium channel block as their primary mechanism of action should be used with caution in\n                    <jats:italic>HCN1<\/jats:italic>\n                    DEE. Other comorbidities of\n                    <jats:italic>HCN1<\/jats:italic>\n                    DEE including retinal dysfunction have also been modelled in\n                    <jats:italic>HCN1<\/jats:italic>\n                    DEE mice, suggesting\n                    <jats:italic>HCN1<\/jats:italic>\n                    variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our understanding of the genetics and pathophysiological mechanisms underlying\n                    <jats:italic>HCN1<\/jats:italic>\n                    epilepsy has progressed significantly and is already influencing therapy. However, more research effort is needed to fully understand the natural histories of\n                    <jats:italic>HCN1<\/jats:italic>\n                    epilepsies and to develop precision therapeutic approaches.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15928-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15928","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T10:25:15Z","timestamp":1691749515000},"page":"3891-3910","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>\n        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