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

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.