Iodide (I−) transport defect (ITD) is an autosomal recessive disorder caused by the inability of the thyroid follicular 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 of thyrocytes. The diagnostic criteria for ITD include a variable degree of hypothyroidism and goiter, low to absent thyroid radioiodide uptake, and low I− saliva-to-serum ratio. Here, we aimed to evaluate mutations in the gene encoding NIS in pediatric patient suspected of ITD on the basis of severely reduced 99mTcO4- accumulation in a eutopic thyroid gland. The index patient showed abnormally high TSH level during neonatal screening (64 μIU/ml). Diagnostic confirmation of congenital hypothyroidism was achieved by measuring serum TSH 203 μIU/ml, FT4 1.6 ng/dl, T4 8.7 μg/dl, and T3 121 ng/dl. Ultrasound showed a normal-sized gland. The analysis of the gene encoding NIS revealed a previously unidentified homozygous G>A transition at nucleotide +1682 in exon 14 (c.1682G>A) resulting in a glutamic acid instead of a glycine at position 561 located in the intracellular carboxy terminus of the protein. Surprisingly, functional analysis revealed that Cos-7 cellsthat do not express endogenous NIStransfected with G561E NIS displayed 125I− uptake levels similar to those of cells expressing WT NIS. Flow cytometry analysis showed that the levels of G561E NIS at the plasma membrane were similar to those of WT NIS. Although the mechanism by which G561E mutation impairs NIS activity is currently unknown, we hypothesized that the negative charge of the Glu residue may interfere the recognition of the dileucine-like sorting motif (L562L563) located in NIS carboxy-terminus by adaptor proteins thus affecting NIS plasma membrane sorting in polarized epithelial cells. Further evaluation of G561E NIS in polarized cells is likely to provide novel evidence regarding NIS targeting to the plasma membrane.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology