{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T06:33:21Z","timestamp":1762065201901,"version":"build-2065373602"},"reference-count":71,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft","award":["KO4576\/1-2"],"award-info":[{"award-number":["KO4576\/1-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dominant KCNQ1 variants are well-known for underlying cardiac arrhythmia syndromes. The two heterozygous KCNQ1 missense variants, R116L and P369L, cause an allelic disorder characterized by pituitary hormone deficiency and maternally inherited gingival fibromatosis. Increased K+ conductance upon co-expression of KCNQ1 mutant channels with the beta subunit KCNE2 is suggested to underlie the phenotype; however, the reason for KCNQ1-KCNE2 (Q1E2) channel gain-of-function is unknown. We aimed to discover the genetic defect in a single individual and three family members with gingival overgrowth and identified the KCNQ1 variants P369L and V185M, respectively. Patch-clamp experiments demonstrated increased constitutive K+ conductance of V185M-Q1E2 channels, confirming the pathogenicity of the novel variant. To gain insight into the pathomechanism, we examined all three disease-causing KCNQ1 mutants. Manipulation of the intracellular Ca2+ concentration prior to and during whole-cell recordings identified an impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. These features were absent in mutant KCNQ1 channels and in wild-type channels co-expressed with calmodulin and exposed to high intracellular Ca2+. Moreover, co-expression of calmodulin with wild-type Q1E2 channels and loading the cells with high Ca2+ drastically increased Q1E2 current amplitudes, suggesting that KCNE2 normally limits the resting Q1E2 conductance by an increased demand for calcified calmodulin to achieve effective channel opening. Our data link impaired Ca2+ sensitivity of the KCNQ1 mutants R116L, V185M and P369L to Q1E2 gain-of-function that is associated with a particular KCNQ1 channelopathy.<\/jats:p>","DOI":"10.3390\/ijms23179690","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T01:39:19Z","timestamp":1661737159000},"page":"9690","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinically Relevant KCNQ1 Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca2+ Sensitivity of the Channel"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-3503","authenticated-orcid":false,"given":"Christiane K.","family":"Bauer","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9550-2270","authenticated-orcid":false,"given":"Tess","family":"Holling","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-8911","authenticated-orcid":false,"given":"Denise","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Human Genetics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt Universit\u00e4t zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-3340","authenticated-orcid":false,"given":"M\u00e1rio N\u00f4ro","family":"La\u00e7o","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra, 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2486-8782","authenticated-orcid":false,"given":"Ebtesam","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 5422031, Egypt"},{"name":"Genetics Department, Armed Forces College of Medicine (AFCM), Cairo 4460015, Egypt"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1967-8893","authenticated-orcid":false,"given":"Omneya Magdy","family":"Omar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria 5422031, Egypt"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5993-7709","authenticated-orcid":false,"given":"Malik","family":"Alawi","sequence":"additional","affiliation":[{"name":"Bioinformatics Core, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8963","authenticated-orcid":false,"given":"Kerstin","family":"Kutsche","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng0196-17","article-title":"Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias","volume":"12","author":"Wang","year":"1996","journal-title":"Nat. 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