Iodide (I^-) transportdefect (ITD) is an autosomal recessive disorder caused by the inability of the thyroidfollicular cell to actively accumulate iodide. Active I^-accumulation is mediated by the Na⁺/I^- symporter (NIS),an integral plasma membrane glycoprotein located on the basolateral surface ofthyrocytes. The diagnostic criteria for ITD include a variable degree ofhypothyroidism and goiter, low to absent thyroid radioiodide uptake, and low I^-saliva-to-serum ratio.

Here, we aimed to evaluatemutations in the gene encoding NIS in pediatric patient suspected of ITD on thebasis of severely reduced ^99mTcO₄^- accumulationin a eutopic thyroid gland. The index patient showed abnormally high TSH level duringneonatal screening (64 µIU/ml). Diagnostic confirmation of congenitalhypothyroidism was achieved by measuring serum TSH 203 µIU/ml, FT₄ 1.6ng/dl, T₄ 8.7 µg/dl, and T₃ 121 ng/dl. Ultrasound showeda normal-sized gland.

The analysis of the gene encodingNIS revealed a previously unidentified homozygous G>A transition atnucleotide +1682 in exon 14 (c.1682G>A) resulting in a glutamic acid insteadof a glycine at position 561 located in the intracellular carboxy terminus ofthe protein.

Surprisingly, functional analysisrevealed that Cos-7 cells?that do not express endogenous NIS?transfected with G561ENIS displayed ¹²⁵I^- uptake levels similar to those ofcells expressing WT NIS. Flow cytometry analysis showed that the levels ofG561E NIS at the plasma membrane were similar to those of WT NIS.

Although the mechanism by which G561Emutation impairs NIS activity is currently unknown, we hypothesized that thenegative charge of the Glu residue may interfere the recognition of the dileucine-likesorting motif (L⁵⁶²L⁵⁶³) located in NIS carboxy-terminus byadaptor proteins thus affecting NIS plasma membrane sorting in polarizedepithelial cells. Further evaluation of G561E NIS in polarized cells is likelyto provide novel evidence regarding NIS targeting to the plasma membrane.