{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:03:46Z","timestamp":1791270226113,"version":"4.1.0"},"reference-count":21,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,6,15]]},"abstract":"<jats:p>\n                    220-kDa ankyrin-B is required for coordinated assembly of Na\/Ca exchanger, Na\/K ATPase, and inositol trisphosphate (Ins\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>3<\/jats:sub>\n                    ) receptor at transverse-tubule\/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics and abnormal localization and expression of Na\/Ca exchanger, Na\/K ATPase, and Ins\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>3<\/jats:sub>\n                    R in ankyrin-B\n                    <jats:sup>+\/-<\/jats:sup>\n                    cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na\/K ATPase, Na\/Ca exchanger, and Ins\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>3<\/jats:sub>\n                    receptor.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402546101","type":"journal-article","created":{"date-parts":[[2004,6,3]],"date-time":"2004-06-03T20:13:28Z","timestamp":1086293608000},"page":"9137-9142","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":276,"title":["A cardiac arrhythmia syndrome caused by loss of ankyrin-B function"],"prefix":"10.1073","volume":"101","author":[{"given":"Peter J.","family":"Mohler","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Splawski","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Bottelli","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Sharpe","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Timothy","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Keating","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vann","family":"Bennett","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neurosciences, Duke University Medical Center, Durham, NC 27710; Howard Hughes Medical Institute and Department of Cardiology, Children's Hospital, Department of Pediatrics and Cell Biology, Harvard Medical School, Boston, MA 02115; Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, 65-27100 Pavia, Italy; and Department of Human Genetics, University of Utah, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,6,3]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(00)00715-4"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.10.1178"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026255617913"},{"key":"e_1_3_2_4_2","first-page":"2041","volume":"289","year":"2003","unstructured":"Moss, A. J. (2003) J. Am. Med. Assoc. 289, 2041-2044.","journal-title":"J. Am. Med. Assoc."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01335"},{"key":"e_1_3_2_6_2","first-page":"1114","volume":"57","year":"1995","unstructured":"Schott, J. J., Charpentier, F., Peltier, S., Foley, P., Drouin, E., Bouhour, J. B., Donnelly, P., Vergnaud, G., Bachner, L., Moisan, J. P., et al. (1995) Am. J. Hum. Genet. 57, 1114-1122.7485162","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(00)00716-6"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1353"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.5.1295"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.5.1305"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.147.5.995"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200109026"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110958200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199705293362204"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00224-3"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085167"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303327200"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.4.441"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60995-0"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)37055-3"},{"key":"e_1_3_2_21_2","unstructured":"Mohler P. J. Hoffman J. A. Davis J. Q. Abdi K. M. Kim C. R. Jones S. K. Davis L. H. Roberts K. F. & Bennett V. (2004) J. Biol. Chem. in press."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0402546101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T22:07:32Z","timestamp":1650924452000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0402546101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,6,3]]},"references-count":21,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2004,6,15]]}},"alternative-id":["10.1073\/pnas.0402546101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0402546101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,6,3]]},"assertion":[{"value":"2004-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-06-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}