{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:49:54Z","timestamp":1779238194193,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2006,11,2]],"date-time":"2006-11-02T00:00:00Z","timestamp":1162425600000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genesis"],"published-print":{"date-parts":[[2006,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>SCN5A<\/jats:italic> encodes the predominant voltage\u2010gated sodium channel isoform in human heart and nearly 100 variants have now been described and studied in vitro. However, development of animal models to analyze function of such large numbers of human gene variants represents a continuing challenge in translational medicine. Here, we describe the implementation of a two stage procedure, recombinase\u2010mediated cassette exchange (RMCE), to efficiently and rapidly generate mice in which a full\u2010length human cDNA replaces expression of the murine ortholog. In the first step of RMCE, conventional homologous recombination in mouse ES cells was used to replace <jats:italic>scn5a<\/jats:italic> exon 2 (that contains the translation start site) with a cassette acceptor that includes the thymidine kinase gene, flanked by loxP\/inverted loxP sites. In the second step, the cassette acceptor site was replaced by the full\u2010length wild\u2010type human <jats:italic>SCN5A<\/jats:italic> cDNA by Cre\/loxP\u2010mediated recombination. The exchange event occurred in 7\/29 (24%) colonies, and the time from electroporation to first homozygotes was only 8 months. PCR\u2010restriction fragment length polymorphism (RFLP) showed that the murine isoform was replaced by the human one, and functional studies indicated that mice with human cardiac sodium channels have wild\u2010type sodium current density, action potential durations, heart rates, and QRS durations. These data demonstrate that RMCE can be used to generate mice in which a targeted allele can be rapidly and efficiently replaced by variants of choice, and thereby can serve as an enabling approach for the functional characterization of ion channel and other DNA variants. genesis 44:556\u2013564, 2006. Published 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/dvg.20247","type":"journal-article","created":{"date-parts":[[2006,11,2]],"date-time":"2006-11-02T19:47:09Z","timestamp":1162496829000},"page":"556-564","source":"Crossref","is-referenced-by-count":18,"title":["Recombinase\u2010mediated cassette exchange to rapidly and efficiently generate mice with human cardiac sodium channels"],"prefix":"10.1002","volume":"44","author":[{"given":"Kai","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Hipkens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagesh","family":"Chopra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjorn","family":"Knollmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Magnuson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,11,2]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V90.9.3332"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.595454"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20003"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3113"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215570"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000050585.07097.D7"},{"key":"e_1_2_1_8_1","volume-title":"Manipulating the mouse embryo: A laboratory manual","author":"Hogan 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