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This work aimed at identifying <jats:italic>SLC12A3<\/jats:italic> variants in the GS pedigree and reveal the effect of the mutations on protein structure and function.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Whole-exome sequencing (WES) and Sanger sequencing were performed in the pedigree. Configuration prediction of two mutant NCC proteins were achieved using SWISS-MODEL. The <jats:italic>SLC12A3<\/jats:italic> missense mutants were generated by site-specific mutagenesis, and the protein expression, location and Na<jats:sup>+<\/jats:sup> uptake activity were assessed by using the HEK293T cell line.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Genetic analysis identified novel compound heterozygous <jats:italic>SLC12A3<\/jats:italic> variants (c.718G\u2009&gt;\u2009A\/p.E240K and c.2675T\u2009&gt;\u2009C\/p.L892P) in the patient with typical GS phenotype. Both of her parents, elder brother and her son carried the heterozygous p.L892P variant, but only the elder brother exhibited mild hypokalemia. Bioinformatics tools predicted that both mutations were highly species conserved and pathogenic. The prediction of mutant protein indicated that p.E240K and p.L892P altered protein\u2019s secondary and three-dimensional (3D) structure and stability. Functional experiments revealed decreased protein expression and Na<jats:sup>+<\/jats:sup> uptake activity caused by these two variants, especially the p.L892P variant.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our study presents the genetic and functional evidence for the novel compound heterozygous loss-of-function variants in <jats:italic>SLC12A3<\/jats:italic> that may synergistically cuase GS, and expands the mutation spectrum of <jats:italic>SLC12A3<\/jats:italic> variants in patients with GS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13023-025-03577-8","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T13:18:06Z","timestamp":1739279886000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional evaluation of novel compound heterozygous variants in SLC12A3 of Gitelman syndrome"],"prefix":"10.1186","volume":"20","author":[{"given":"Na","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanxing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuaishuai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juping","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haixia","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"3577_CR1","doi-asserted-by":"publisher","unstructured":"Knoers NV, Levtchenko EN. 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Written informed consent was obtained from all subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"66"}}