{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T14:08:18Z","timestamp":1748614098759,"version":"3.40.5"},"reference-count":49,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM121322","U54GM104942"],"award-info":[{"award-number":["P20GM121322","U54GM104942"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["13GRNT16420018"],"award-info":[{"award-number":["13GRNT16420018"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Arrhythmia"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Missense mutations in the hyperpolarization\u2010activated cyclic nucleotide\u2010modulated (HCN) channel 4 (HCN4) are one of the genetic causes of cardiac sinus bradycardia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate possible HCN4 channel mutation in a young patient with profound sinus bradycardia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Direct sequencing of <jats:italic>HCN4<\/jats:italic> and whole\u2010exome sequencing were performed on DNA samples from the indexed patient (P), the patient's son (PS), and a family unrelated healthy long\u2010distance running volunteer (V). Resting heart rate was 31\u00a0bpm for P, 67\u00a0bpm for PS, and 50\u00a0bpm for V. Immunoblots, flow cytometry, and immunocytofluorescence confocal imaging were used to study cellular distribution of channel variants. Patch\u2010clamp electrophysiology was used to investigate the properties of mutant HCN1 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In P no missense mutations were found in the HCN4 gene; instead, we found two heterozygous variants in the HCN1 gene: deletion of an N\u2010terminal glycine triplet (<jats:sup>72<\/jats:sup>GGG<jats:sup>74<\/jats:sup>, \u201cN\u2010del\u201d) and a novel missense variant, P851A, in the C\u2010terminal region. N\u2010del variant was found before and shared by PS. These two variations were not found in V. Compared to wild type, N\u2010del and P851A reduced cell surface expression and negatively shifted voltage\u2010activation with slower activation kinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Decreased channel activity HCN1 mutant channel makes it unable to contribute to early depolarization of sinus node action potential, thus likely a main cause of the profound sinus bradycardia in this patient.<\/jats:p><\/jats:sec>","DOI":"10.1002\/joa3.12598","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T08:00:41Z","timestamp":1626163241000},"page":"1337-1347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Contribution of HCN1 variant to sinus bradycardia: A case 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8226-2319","authenticated-orcid":false,"given":"Quincy","family":"Hathaway","sequence":"additional","affiliation":[{"name":"Department of Exercise Physiology School of Medicine West Virginia University Morgantown WV USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Brundage","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology &amp; Cell Biology School of Medicine West Virginia University Morgantown WV USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Ammer","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology &amp; Cell Biology School of Medicine West Virginia University Morgantown WV USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Mathers","sequence":"additional","affiliation":[{"name":"Department of 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