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CS is caused by gain\u2010of\u2010function (GOF) variants in <jats:italic>KCNJ8<\/jats:italic> or <jats:italic>ABCC9<\/jats:italic> that encode pore\u2010forming Kir6.1 and regulatory SUR2 subunits of ATP\u2010sensitive potassium (K<jats:sub>ATP<\/jats:sub>) channels. A novel heterozygous <jats:italic>ABCC9<\/jats:italic> variant, c.2440G&gt;T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside\u2010out patch\u2010clamp assays of K<jats:sub>ATP<\/jats:sub> channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP\u2010binding cassette (ABC) protein ion channels.<\/jats:p>","DOI":"10.1002\/ajmg.a.63815","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T08:54:08Z","timestamp":1721379248000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel <i>ABCC9<\/i> variant in a <scp>Greek<\/scp> family with <scp>Cantu<\/scp> syndrome affecting multiple generations highlights the functional role of the <scp>SUR2B NBD1<\/scp>"],"prefix":"10.1002","volume":"194","author":[{"given":"Jian","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Center for the Investigation of Membrane Excitability Diseases Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athina","family":"Ververi","sequence":"additional","affiliation":[{"name":"Department for Genetics of Rare Diseases Papageorgiou General Hospital  Thessaloniki Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Center for the Investigation of Membrane Excitability Diseases Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Tryon","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Center for the Investigation of Membrane Excitability Diseases Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandros","family":"Sotiriadis","sequence":"additional","affiliation":[{"name":"Second Department of Obstetrics and Gynecology Aristotle University of Thessaloniki, Ippokrateio Hospital  Thessaloniki Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Rouvalis","sequence":"additional","affiliation":[{"name":"Paediatric Cardiology Practice  Thessaloniki Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7425-6322","authenticated-orcid":false,"given":"Dorothy K.","family":"Grange","sequence":"additional","affiliation":[{"name":"Center for the Investigation of Membrane Excitability Diseases Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Department of Pediatrics, Division of Genetics and Genomic Medicine Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Giannios","sequence":"additional","affiliation":[{"name":"Department of Developmental Paediatrics Naval Hospital of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-2134","authenticated-orcid":false,"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology Washington University in St. Louis  St. Louis Missouri USA"},{"name":"Center for the Investigation of Membrane Excitability Diseases Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1998.78.1.227"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3230777"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1681.2002.03650.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00038.2023"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.45.10.1439"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511495"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP279612"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39379-4"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2009"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00003.2015"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-022-01210-x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.123.001659"},{"key":"e_1_2_9_14_1","volume-title":"GeneReviews(R)","author":"Grange D. 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