Iodide transport defect: functional characterization of a novel mutation in the Na+/I- symporter 5'-untranslated region in a patient with congenital hypothyroidism.

CONTEXT: Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD.

OBJECTIVE

Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype.

DESIGN

The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed.

RESULTS

The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5'-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency.

CONCLUSIONS

We described a novel mutation in the 5'-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function.