{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:07:25Z","timestamp":1784293645789,"version":"3.55.0"},"reference-count":51,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["HL140024"],"award-info":[{"award-number":["HL140024"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,8]]},"abstract":"<jats:p>\n                    Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1,\n                    <jats:italic>KCNJ8<\/jats:italic>\n                    ) and accessory (SUR2,\n                    <jats:italic>ABCC9<\/jats:italic>\n                    ) ATP-sensitive potassium (K\n                    <jats:sub>ATP<\/jats:sub>\n                    ) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR\/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse\n                    <jats:italic>ABCC9<\/jats:italic>\n                    gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower K\n                    <jats:sub>ATP<\/jats:sub>\n                    current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and K\n                    <jats:sub>ATP<\/jats:sub>\n                    in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent K\n                    <jats:sub>ATP<\/jats:sub>\n                    channel activity. Surprisingly, sequencing of SUR2 cDNA revealed 2 distinct transcripts, one encoding full-length SUR2 protein; and the other with an in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in approximately 40% and approximately 90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in nonfunctional channels. CS tissue from SUR2[R1154Q] mice and human induced pluripotent stem cell\u2013derived (hiPSC-derived) cardiomyocytes showed only full-length SUR2 transcripts, although further studies will be required in order to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.145934","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T12:06:37Z","timestamp":1612267597000},"source":"Crossref","is-referenced-by-count":15,"title":["Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice"],"prefix":"10.1172","volume":"6","author":[{"given":"Haixia","family":"Zhang","sequence":"first","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Hanson","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias Scherf","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Center for Biochemistry and Molecular Cell Biology, Heart Research Center G\u00f6ttingen, University Medicine G\u00f6ttingen, G\u00f6ttingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Emfinger","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0859-3854","authenticated-orcid":true,"given":"Conor","family":"McClenaghan","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7039-2236","authenticated-orcid":true,"given":"Theresa","family":"Harter","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Yan","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Site G\u00f6ttingen, G\u00f6ttingen, Germany."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4807-6317","authenticated-orcid":true,"given":"Paige E.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases and"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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