{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:38:00Z","timestamp":1780447080624,"version":"3.54.1"},"reference-count":16,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Inappropriate sinus tachycardia (IST) is an arrhythmia characterized by rapid sinus rates of over 100 bpm at rest. The mechanisms underlying this often-debilitating condition are not fully understood. The differential diagnosis for this persistent observation is broad, including medication side effects or serendipitous use of chronotropic stimulating drugs. Genetic causes of IST are seldom considered. Only 2 mutations have been linked to this condition, both of which affect the gene encoding\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      channels, which play an important role in generating pacemaker activity of the sinoatrial node.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Standard clinical genetic testing was performed on a child with IST, her affected mother, and 2 healthy siblings. A novel\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      channel variant identified in the family was studied by whole-cell patch clamp analysis. Three-dimensional protein structures of mutant and wild-type\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      channels were generated and subjected to 200 ns of unrestricted molecular dynamics simulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      A heterozygous, missense variant was identified in the\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      gene (p.N299S) in the affected child and mother, while absent in 2 healthy siblings of the child. Patch clamp analysis revealed significantly increased\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      current density and a rightward-shifted activation curve in cells expressing p.N299S-\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      versus wild-type channels, suggesting constitutive activity of the mutant\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      channel. In molecular dynamics simulations, the voltage sensor of p.N299S-\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      channels adopted a resting conformation mimicking that of cAMP-bound wild-type\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      , providing a structural basis for the functional observations. Ivabradine application returned the gain-of-function properties of mutant channels to baseline levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      We identified a gain-of-function\n                      <jats:italic toggle=\"yes\">HCN4<\/jats:italic>\n                      variant in a family with IST that displays constitutive activity and structurally mimics the effects of cAMP activation. This study furthers our understanding of the mechanisms underlying IST and provides data supporting the efficacious effect of ivabradine in genetically based IST.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.125.013899","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T09:00:37Z","timestamp":1760432437000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["HCN4 Mutation Causing Familial Inappropriate Sinus Tachycardia Leads to a Conformational Change Mimicking cAMP Binding and Induces Constitutive Channel Activity"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4063-5935","authenticated-orcid":true,"given":"Sara L.","family":"Bober","sequence":"first","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Department of Medicine, Toronto General Hospital, Canada (S.L.B., Q.L., T.F., M.H.G.)."},{"name":"Department of Physiology, University of Toronto, Canada (S.L.B., Q.L., T.F., M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuju","family":"Li","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Department of Medicine, Toronto General Hospital, Canada (S.L.B., Q.L., T.F., M.H.G.)."},{"name":"Department of Physiology, University of Toronto, Canada (S.L.B., Q.L., T.F., M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ros-Pardo","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), Madrid, Spain (D.R.-P., I.M.-A., P.G.-P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trent","family":"Faultless","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Department of Medicine, Toronto General Hospital, Canada (S.L.B., Q.L., T.F., M.H.G.)."},{"name":"Department of Physiology, University of Toronto, Canada (S.L.B., Q.L., T.F., M.H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0674-6423","authenticated-orcid":true,"given":"\u00cd\u00f1igo","family":"Marcos-Alcalde","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), Madrid, Spain (D.R.-P., I.M.-A., P.G.-P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-729X","authenticated-orcid":true,"given":"Paulino","family":"G\u00f3mez-Puertas","sequence":"additional","affiliation":[{"name":"Molecular Modeling Group, Centro de Biologia Molecular Severo Ochoa (CBM, CSIC-UAM), Madrid, Spain (D.R.-P., I.M.-A., P.G.-P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0242-5208","authenticated-orcid":true,"given":"Michael H.","family":"Gollob","sequence":"additional","affiliation":[{"name":"Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Department of Medicine, Toronto General Hospital, Canada (S.L.B., Q.L., T.F., M.H.G.)."},{"name":"Department of Physiology, University of Toronto, Canada (S.L.B., Q.L., T.F., 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