Iodide transport defect (ITD) is an autosomal recessive disorder caused by an impaired Na+/I- symporter (NIS)-mediated active iodide accumulation into thyrocytes. We analyze the presence of NIS gene mutations in six patients with congenital hypothyroidism, goiter and reduced to absent 99mTcO4- uptake. Genomic DNA encoding NIS sequence was evaluated. The analysis revealed the presence of an undescribed homozygous C to T transition at position -54 located in the 5’ untranslated region in one patient. Functional analysis performed in NIS cDNA wild-type (WT) or mutated (-54C→T)-transfected COS-7 cells showed that the mutant only concentrated 10% of WT levels (125Iodide), suggesting a direct role of the mutation as cause of ITD. The mutation severely impaired NIS protein expression (Western blot). NIS mRNA levels (RT/qPCR) were similar in the carrying NIS mutated sequence and WT cells, proposing a translational deficiency exerted by the mutation. NIS mRNA polysomal profile analysis in transfected cells demonstrated a significantly reduced mutant NIS mRNA levels in polysomes, consistent with a reduced translation rate and a subsequent reduced protein expression. Moreover, our results support the possibility that alterations of proteins related to NIS targeting to the plasma membrane could also account as potential causes of ITD.
