{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:50:20Z","timestamp":1791978620415,"version":"4.4.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background and Objectives<\/jats:title><jats:p>Defects in the human sodium\/iodide symporter (<jats:italic>SLC5A5<\/jats:italic>) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify <jats:italic>SLC5A5<\/jats:italic> mutations in Chinese patients with CH and to evaluate the function of the mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two hundred and seventy-three patients with primary CH were screened for mutations in <jats:italic>SLC5A5<\/jats:italic> using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in <jats:italic>SLC5A5<\/jats:italic>. The functional activity of the mutants was further examined <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in <jats:italic>SLC5A5<\/jats:italic> were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. <jats:italic>In vitro<\/jats:italic> experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The undescribed compound heterozygous mutation of <jats:italic>SLC5A5<\/jats:italic> was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of <jats:italic>SLC5A5<\/jats:italic> in CH pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.620117","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T16:37:41Z","timestamp":1616171861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism"],"prefix":"10.3389","volume":"12","author":[{"given":"Cao-Xu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Xiu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Run","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Jia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Yao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Zhang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huai-Dong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.clp.2017.10.004","article-title":"Congenital Hypothyroidism","volume":"45","author":"Wassner","year":"2018","journal-title":"Clinics Perinatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034125","article-title":"The Sodium\/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications","volume":"79","author":"Ravera","year":"2017","journal-title":"Annu Rev Physiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.1358","article-title":"Cloning of the human sodium lodide symporter","volume":"226","author":"Smanik","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.35.22657","article-title":"N-linked glycosylation of the thyroid Na+\/I- symporter (NIS). Implications for its secondary structure model","volume":"273","author":"Levy","year":"1998","journal-title":"J Biol Chem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/biof.5520100228","article-title":"Molecular and cellular mechanisms of transepithelial iodide transport in the thyroid","volume":"10","author":"Nilsson","year":"1999","journal-title":"BioFactors (Oxford England)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/379458a0","article-title":"Cloning and characterization of the thyroid iodide transporter","volume":"379","author":"Dai","year":"1996","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.11.5568","article-title":"Characterization of the thyroid Na+\/I- symporter with an anti-COOH terminus antibody","volume":"94","author":"Levy","year":"1997","journal-title":"Proc Natl Acad Sci U States America"},{"key":"B8","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1210\/er.2001-0029","article-title":"The sodium\/iodide Symporter (NIS): characterization, regulation, and medical significance","volume":"24","author":"Doh\u00e1n","year":"2003","journal-title":"Endocr Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/er.2012-1036","article-title":"The Na+\/I- symporter (NIS): mechanism and medical impact","volume":"35","author":"Portulano","year":"2014","journal-title":"Endocr Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.mce.2010.02.007","article-title":"Genetics and phenomics of hypothyroidism and goiter due to NIS mutations","volume":"322","author":"Spitzweg","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0046","article-title":"Novel Sodium\/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism","volume":"29","author":"Martin","year":"2019","journal-title":"Thyroid"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0137","article-title":"A Novel Missense Mutation in the SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism","volume":"28","author":"Watanabe","year":"2018","journal-title":"Thyroid"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2000.10.471","article-title":"A novel V59E missense mutation in the sodium iodide symporter gene in a family with iodide transport defect","volume":"10","author":"Fujiwara","year":"2000","journal-title":"Thyroid"},{"key":"B14","doi-asserted-by":"publisher","first-page":"K1","DOI":"10.1530\/EJE-20-0255","article-title":"First case of fetal goitrous hypothyroidism due to SLC5A5\/NIS mutations","volume":"183","author":"Stoupa","year":"2020","journal-title":"Eur J Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.83.9.5243","article-title":"Novel, missense and loss-of-function mutations in the sodium\/iodide symporter gene causing iodide transport defect in three Japanese patients","volume":"83","author":"Kosugi","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.84.9.3248","article-title":"A novel mutation in the sodium\/iodide symporter gene in the largest family with iodide transport defect","volume":"84","author":"Kosugi","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7594","article-title":"Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium\/iodide symporter gene","volume":"240","author":"Pohlenz","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0027","article-title":"Molecular characterization of V59E NIS, a Na+\/I- symporter mutant that causes congenital I- transport defect","volume":"149","author":"Reed-Tsur","year":"2008","journal-title":"Endocrinology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108278108","article-title":"Mechanism of anion selectivity and stoichiometry of the Na+\/I- symporter (NIS)","volume":"108","author":"Paroder-Belenitsky","year":"2011","journal-title":"Proc Natl Acad Sci U States America"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.120246","article-title":"The iodide-transport-defect-causing mutation R124H: a \u03b4-amino group at position 124 is critical for maturation and trafficking of the Na+\/I- symporter","volume":"126","author":"Paroder","year":"2013","journal-title":"J Cell Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00898","article-title":"The Q267E mutation in the sodium\/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number","volume":"117","author":"De La Vieja","year":"2004","journal-title":"J Cell Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1824","article-title":"Sodium\/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency","volume":"100","author":"Nicola","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/S0014-5793(98)00522-5","article-title":"Identification of a structural requirement for thyroid Na+\/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism","volume":"429","author":"Levy","year":"1998","journal-title":"FEBS Lett"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700147200","article-title":"Amino acid residues in transmembrane segment IX of the Na+\/I- symporter play a role in its Na+ dependence and are critical for transport activity","volume":"282","author":"De la Vieja","year":"2007","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.beem.2017.03.006","article-title":"Iodide handling disorders (NIS, TPO, TG, IYD)","volume":"31","author":"Targovnik","year":"2017","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2019.07.031","article-title":"Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism","volume":"497","author":"Fang","year":"2019","journal-title":"Clinica chimica acta; Int J Clin Chem"},{"key":"B27","doi-asserted-by":"publisher","first-page":"110761","DOI":"10.1016\/j.mce.2020.110761","article-title":"The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism","volume":"506","author":"Zhang","year":"2020","journal-title":"Mol Cell Endocrinol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-1017","article-title":"The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes","volume":"178","author":"Sun","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.4.8435","article-title":"Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome","volume":"87","author":"Taylor","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2003.01877.x","article-title":"Congenital hypothyroidism due to a new deletion in the sodium\/iodide symporter protein","volume":"59","author":"Tonacchera","year":"2003","journal-title":"Clin Endocrinol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinf (Oxford England)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1832","article-title":"Extending the clinical heterogeneity of iodide transport defect (ITD): a novel mutation R124H of the sodium\/iodide symporter gene and review of genotype-phenotype correlations in ITD","volume":"91","author":"Szinnai","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0349","article-title":"Iodide transport defect: functional characterization of a novel mutation in the Na+\/I- symporter 5\u2019-untranslated region in a patient with congenital hypothyroidism","volume":"96","author":"Nicola","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0071","article-title":"Na(+)\/I(-) symporter activity requires a small and uncharged amino acid residue at position 395","volume":"16","author":"Doh\u00e1n","year":"2002","journal-title":"Mol Endocrinol (Baltimore Md)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160406","article-title":"The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+\/sugar symport","volume":"321","author":"Faham","year":"2008","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature03978","article-title":"Crystal structure of a bacterial homologue of Na+\/Cl\u2013dependent neurotransmitter transporters","volume":"437","author":"Yamashita","year":"2005","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature09580","article-title":"The mechanism of sodium and substrate release from the binding pocket of vSGLT","volume":"468","author":"Watanabe","year":"2010","journal-title":"Nature"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.620117\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T16:37:44Z","timestamp":1616171864000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.620117\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,19]]},"references-count":37,"alternative-id":["10.3389\/fendo.2021.620117"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.620117","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,19]]},"article-number":"620117"}}