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Pathogenic variants in the SLC5A5 gene cause iodide transport defects (ITDs). A heterozygous G288S NIS variant was identified in a Spanish family in which female carriers developed thyroid dysfunction during pregnancy. Here, we characterized the functional significance of the G288S variant and other substitutions at residue 288 of human NIS. Human NIS (hNIS) expression and maturation were analyzed by immunoblotting, its subcellular localization was analyzed by immunofluorescence and flow cytometry, and its activity was analyzed by radioiodide uptake assays. The G288S variant does not affect hNIS maturation, membrane trafficking, or I\u2212 uptake capacity, but significantly reduces I\u2212 affinity while preserving substantial transport activity. In contrast, substitutions introducing charged residues (arginine, aspartic acid, or glutamic acid) or proline severely disrupted NIS maturation, plasma membrane targeting, and iodide transport. Because the variant was identified in heterozygosity, we evaluated residue 288 substitutions under heterozygous-like conditions. Co-expression of the patient-derived G288S variant with WT NIS produced an intermediate apparent Km without reducing Vmax compared with WT, consistent with a modest co-expression-dependent kinetic effect rather than a strong dominant-negative mechanism. In contrast, the severely disruptive G288E substitution reduced cell-surface NIS expression under co-expression conditions, providing proof-of-principle evidence that severe alteration of residue 288 can impair NIS plasma membrane delivery. These findings highlight residue 288 as a key determinant of hNIS functionality and underscore the need to carefully evaluate heterozygous SLC5A5\/NIS variants, as they may become clinically relevant under conditions of increased physiological iodine demand and contribute to partial iodide transport impairment.<\/jats:p>","DOI":"10.3390\/ijms27125160","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:43:46Z","timestamp":1780897426000},"page":"5160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["New Insights into Iodide Transport Defects (ITDs) from the Characterization of a Heterozygous NIS Missense Variant (p.G288S) Identified in a Family with Thyroid Dysfunction During Pregnancy"],"prefix":"10.3390","volume":"27","author":[{"given":"Maddi","family":"Garate-Etxeberria","sequence":"first","affiliation":[{"name":"Tumor Endocrine Unit, Chronic Disease Program (UFIEC), Instituto de Salud Carlos III, Ctra. Majadahonda a Pozuelo km 2.2, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9171-2606","authenticated-orcid":false,"given":"Mari Paz","family":"Lopez-Molina","sequence":"additional","affiliation":[{"name":"Tumor Endocrine Unit, Chronic Disease Program (UFIEC), Instituto de Salud Carlos III, Ctra. Majadahonda a Pozuelo km 2.2, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Hortiguela","sequence":"additional","affiliation":[{"name":"Tumor Endocrine Unit, Chronic Disease Program (UFIEC), Instituto de Salud Carlos III, Ctra. Majadahonda a Pozuelo km 2.2, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pouya","family":"Alikhani","sequence":"additional","affiliation":[{"name":"Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"De la Calle","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Custodia","family":"Garc\u00eda-Jimenez","sequence":"additional","affiliation":[{"name":"Area of Physiology, Faculty of Health Sciences, University Rey Juan Carlos (URJC), 28922 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Carlos","family":"Moreno","sequence":"additional","affiliation":[{"name":"Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital Research Institute (IdiPAZ), 28029 Madrid, Spain"},{"name":"U-753 The Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1187-1907","authenticated-orcid":false,"given":"Antonio","family":"De la Vieja","sequence":"additional","affiliation":[{"name":"Tumor Endocrine Unit, Chronic Disease Program (UFIEC), Instituto de Salud Carlos III, Ctra. Majadahonda a Pozuelo km 2.2, 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1172\/JCI60047","article-title":"Mechanisms of Thyroid Hormone Action","volume":"122","author":"Brent","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.semcdb.2011.07.009","article-title":"The Role of Iodine in Human Growth and Development","volume":"22","author":"Zimmermann","year":"2011","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101430","DOI":"10.1016\/j.beem.2020.101430","article-title":"Iodine Status and Supplementation before, during, and after Pregnancy","volume":"34","author":"Pearce","year":"2020","journal-title":"Best. Pract. Res. Clin. Endocrinol. 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