{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:36:26Z","timestamp":1791142586934,"version":"4.1.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2007,1,30]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Mutations in the ankyrin-B gene (\n            <jats:italic>ANK2<\/jats:italic>\n            ) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of\n            <jats:italic>ANK2<\/jats:italic>\n            variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific\n            <jats:italic>ANK2<\/jats:italic>\n            variants.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            We performed a comprehensive screen of\n            <jats:italic>ANK2<\/jats:italic>\n            in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified\n            <jats:italic>ANK2<\/jats:italic>\n            variants. We identified 7 novel nonsynonymous\n            <jats:italic>ANK2<\/jats:italic>\n            variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human\n            <jats:italic>ANK2<\/jats:italic>\n            loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous\n            <jats:italic>ANK2<\/jats:italic>\n            variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            We present the first description of differences in cellular phenotypes conferred by specific\n            <jats:italic>ANK2<\/jats:italic>\n            variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify\n            <jats:italic>ANK2<\/jats:italic>\n            variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of \u201cankyrin-B syndrome,\u201d and reinforce the role of ankyrin-B\u2013dependent protein interactions in regulating cardiac electrogenesis.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.106.656512","type":"journal-article","created":{"date-parts":[[2007,1,23]],"date-time":"2007-01-23T01:52:16Z","timestamp":1169517136000},"page":"432-441","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":145,"title":["Defining the Cellular Phenotype of \u201cAnkyrin-B Syndrome\u201d Variants"],"prefix":"10.1161","volume":"115","author":[{"given":"Peter J.","family":"Mohler","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solena","family":"Le Scouarnec","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Denjoy","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Lowe","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Guicheney","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise","family":"Caron","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona M.","family":"Driskell","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Schott","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris","family":"Norris","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Leenhardt","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Kim","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Escande","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine (P.J.M., J.S.L., I.M.D.), University of Iowa College of Medicine, Iowa City; Departments of Medicine and Pharmacology and Oates Institute for Experimental Therapeutics (K.N., R.B.K., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn; INSERM U533 (S.L.S., L.C., J.-J.S., D.E.), L\u2019institut du Thorax, Nantes, France; INSERM U582 (I.D., P.G.), Institut de Myologie, Groupe Hospitalier Pitie\u0301-Salpe\u0302trie\u0300re, Paris, France; AP-HP (I.D., A.L.); Service..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1302.008"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00243-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(00)00715-4"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00002.2005"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1353"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.8.1565"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402546101"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01335"},{"key":"e_1_3_2_9_2","first-page":"1114","volume":"57","year":"1995","unstructured":"Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, Donnelly P, Vergnaud G, Bachner L, Moisan JP, Le Marec H, Pascal O. Mapping of a gene for long QT syndrome to chromosome 4q25\u201327. Am J Hum Genet. 1995; 57: 1114\u20131122.","journal-title":"Am J Hum Genet"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000014448.19052.4c"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.01.005"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110958200"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313979200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401296200"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406018200"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc0702.105124"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.99.4.529"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.07.026"},{"key":"e_1_3_2_19_2","first-page":"2158","volume":"3","year":"2005","unstructured":"Mohler PJ, Davis JQ, Bennett V. Ankyrin-B coordinates the Na\/K ATPase, Na\/Ca exchanger, and InsP(3) receptor in a cardiac T-tubule\/SR microdomain. PLoS Biol. 2005; 3: 2158\u20132167.","journal-title":"PLoS Biol"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506697200"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60995-0"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)37055-3"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25539"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2004.01.001"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.106.656512","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:15:08Z","timestamp":1715577308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.106.656512"}},"subtitle":["Human\n            <i>ANK2<\/i>\n            Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes"],"short-title":[],"issued":{"date-parts":[[2007,1,30]]},"references-count":24,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2007,1,30]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.106.656512"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.106.656512","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,1,30]]},"assertion":[{"value":"2007-01-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}