{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:26:40Z","timestamp":1791217600233,"version":"4.1.0"},"reference-count":20,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,3,12]]},"abstract":"<jats:p>\n                    We describe a mutation (E299V) in\n                    <jats:italic>KCNJ2<\/jats:italic>\n                    , the gene that encodes the strong inward rectifier K\n                    <jats:sup>+<\/jats:sup>\n                    channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of\n                    <jats:italic>KCNJ2<\/jats:italic>\n                    that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I\n                    <jats:sub>K1<\/jats:sub>\n                    at potentials above \u221255 mV (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His\u2013Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1218154110","type":"journal-article","created":{"date-parts":[[2013,2,26]],"date-time":"2013-02-26T00:41:51Z","timestamp":1361839311000},"page":"4291-4296","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":143,"title":["<i>KCNJ2<\/i>\n                    mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia"],"prefix":"10.1073","volume":"110","author":[{"given":"Makarand","family":"Deo","sequence":"first","affiliation":[{"name":"Department of Engineering, Norfolk State University, Norfolk, VA 23504;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfei","family":"Ruan","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program, Leon Charney Division of Cardiology, New York University, New York, NY 10016 ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep V.","family":"Pandit","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushal","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Engineering, Norfolk State University, Norfolk, VA 23504;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Berenfeld","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Blaufox","sequence":"additional","affiliation":[{"name":"Alexandra and Steven Cohen Children\u2019s Medical Center of New York, New Hyde Park, NY 11040;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cerrone","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program, Leon Charney Division of Cardiology, New York University, New York, NY 10016 ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami F.","family":"Noujaim","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Denegri","sequence":"additional","affiliation":[{"name":"Molecular Cardiology, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico, 27100 Pavia, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Jalife","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Program, Leon Charney Division of Cardiology, New York University, New York, NY 10016 ;"},{"name":"Molecular Cardiology, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico, 27100 Pavia, Italy;"},{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,2,25]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.109.921056"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr076"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000162101.76263.8c"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.291.5502.316"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1411"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-009-9829-4"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01237.2009"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253955"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.029355"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1244"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0645h.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr329"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.05.054"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.156075"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708153105"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr008"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.966820"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M901586200"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00658.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002061"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1218154110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T22:32:50Z","timestamp":1649802770000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1218154110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,25]]},"references-count":20,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,3,12]]}},"alternative-id":["10.1073\/pnas.1218154110"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1218154110","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,25]]},"assertion":[{"value":"2013-02-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}