Elsevier

Biochimie

Volume 81, Issue 5, May 1999, Pages 469-476
Biochimie

Original article
Mutations in the sodium/iodide symporter (NIS) gene as a cause for iodide transport defects and congenital hypothyroidism

https://doi.org/10.1016/S0300-9084(99)80097-2Get rights and content

Abstract

The ability to concentrate iodide actively is a characteristic feature of the thyroid gland and several other tissues. This function is mediated through the sodium iodide symporter (NIS), a protein that is located in the basolateral membrane of the thyrocyte. A defect in the NIS (iodide trapping defect) can result in hypothyroidism, the severity of which is variable and influenced, in part, by the amount of iodine supply. The molecular cloning of NIS and characterization of its genomic organization allowed the identification of NIS gene mutations in patients expressing the phenotype of iodide trapping defect. Six mutations (G93R, Q267E, C272X, T354P, Y531X and G543E) have been so far identified and their properties have been partially characterized. G93R, Q267E and Y531X were found in a compound heterozygous individual with NIS defect, C272X and G543E were detected in a homozygous state and T354P has been identified in both homozygotes and heterozygotes in combination with G93R. Heterozygous family members, expressing one normal allele, are clinically not affected. This was confirmed by in vitro analysis where all six mutants produced NISs with virtually no biological activity that did not interfere with the wild-type NIS function when cotransfected in mammalian cells. While the precise mechanisms by which mutant NISs cause iodide trapping defect are still unknown, preliminary data suggest that 354P interferes with the iodide transport function rather than targeting to the cell membrane.

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).

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