Original articleMutations in the sodium/iodide symporter (NIS) gene as a cause for iodide transport defects and congenital hypothyroidism
Section snippets
Physiology, the gene and mutations
Active iodide (I–) transport is the first step in the biosynthesis of thyroid hormone. It is mediated through the sodium/iodide symporter (NIS), a protein that is located in the basolateral membrane of the thyrocyte. Because I– is transported into the cell against concentration and electrical gradients, this transport requires energy. NIS couples the energy that is released by the simultaneous transport of Na + downhill its electrochemical gradient with I– transport, thus, maintaining the I–
Clinical aspects and methods of diagnosis
Although Federman et al suspected iodide trapping defect in a goitrous cretin reported in 1958 [18], the nature of the defect was demonstrated by Stanbury and Chapman 2 years later [19]. Newborns are brought to medical attention because of a high blood TSH level detected during neonatal screening. In children, attention is drawn by delayed development or growth and by the appearance of neck enlargement. In adults, frank hypothyroidism, enlargement of the thyroid gland or a thyroid nodule may be
3. Tissue diagnosis and methods for identification of mutations and their functional analysis
Formerly, the tissue diagnosis of iodide trapping defect was based on the studies carried out on thyroid slices. A defect in I– transport could be identified from the low amount of radioiodide taken up by the tissue as compared to that in the incubation medium. Total iodine and thyroglobulin content are also low but this finding is not diagnostic.
Currently, definitive diagnosis is based on the identification of a mutation in the NIS gene and on the in vitro demonstration of the resulting
Genotype and functional analyses
Sequencing of NIS from genomic DNA as well as cDNA allowed to identify the consequence of a single nucleotide substitution in the coding sequence of the gene that could not have been deduced from the genomic sequence alone. A C to G transversion in nucleotide 1940 (nucleotide numbers are those published for the human NIS cDNA [7]), located in exon 13, predicts a stop (TAC → TAG) in codon 531 (Y531X). The sequence of cDNA, however, showed a 67 bp deletion upstream of the substituted nucleotide.
Possible mechanisms of loss-of-function in NIS molecules and correlation of the phenotype to the genotype
Although six mutations in the NIS gene have been identified and studied in vitro, the mechanisms by which these mutants cause loss of function have not been fully elucidated. The following three possibilities could be considered as a cause for loss-of-function in the NIS molecule: 1) the mutant NIS protein may not be expressed at all; 2) the mutant NIS may not be targeted to the cell membrane; and 3) the mutant protein though properly expressed in the membrane may have lost function because of
Prevalence and genotyping for NIS mutations
The frequency of mutations in the NIS gene is not known. Because heterozygous individuals do not express the phenotype, NIS gene defects can be detected only when both alleles are affected. Furthermore, under conditions of high I– intake, when full preservation of I– concentrating function is not required to achieve normal hormone synthesis, mutations causing partial loss of function may not be detected even in the homozygous individual. Thus, impairment of thyroidal I– concentration requires
Acknowledgements
This work was supported in part by grants from the National Institutes of Health USA (DK-15070 and RR-00055). J. Pohlenz was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Po 556/1-1).
References (25)
- et al.
The mediator of thyroidal iodide accumulation: the sodium/iodide symporter
- et al.
N-linked glycosylation of the thyroid Na+/I- symporter (NIS): implications for its secondary structure model
J. Biol. Chem.
(1998) - et al.
Cloning of the human sodium iodide symporter
Biochem. Biophys. Res. Commun.
(1996) - et al.
Membrane topology of the Na+/glucose cotransporter SGLT1
J. Biol. Chem.
(1996) - et al.
Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene
Biochem. Biophys. Res. Commun.
(1997) - et al.
Congenital hypothyroidism with goitre: absense of an iodide-concentrating mechanism
Lancet
(1960) - et al.
Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism
FEBS Lett.
(1998) Transport of iodide and other anions in the thyroid gland
Physiol. Rev.
(1964)- et al.
The iodide channel of the thyroid. II. Selective iodide conductance inserted into liposomes
Am. J. Physiol.
(1995) - et al.
The modulation of the human sodium iodide symporter activity by Graves' disease sera
J. Clin. Endocrinol. Metab.
(1998)
Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter
Endocrinology
Sequence and structure of a human glucose transporter
Science
Cited by (61)
Identification of a second substrate-binding Site in solute-sodium symporters
2015, Journal of Biological ChemistryMechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals
2013, Toxicology in VitroCitation Excerpt :Competitive inhibition of NIS-mediated iodide uptake by specific anions, for example, blocks not only thyroidal iodide uptake but impairs TH synthesis (Alexander and Wolff, 1966; De Groef et al., 2006; Tonacchera et al., 2004; Wolff, 1998). In the human, mutations in the NIS protein are associated with congenital iodide transport defect, a condition characterized by low iodide uptake, hypothyroidism and goitre (Bizhanova and Kopp, 2009; De La Vieja et al., 2000; Pohlenz and Refetoff, 1999). The classical assay to test the ability of a chemical to interfere with NIS-mediated iodide uptake is based on the measurement of radioiodine (125I−) uptake in NIS-expressing cells (Atterwill and Fowler, 1990; Schmutzler et al., 2007b).
Genetics and phenomics of hypothyroidism and goiter due to NIS mutations
2010, Molecular and Cellular EndocrinologyDisorders of the Thyroid in the Newborn and Infant
2008, Pediatric EndocrinologyPseudodominant inheritance of goitrous congenital hypothyroidism caused by TPO mutations: Molecular and in silico studies
2008, Journal of Clinical Endocrinology and MetabolismFlavonoids in the development and control of autoimmunity
2023, Archivos de Alergia e Inmunologia Clinica