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

NICOLA, JP; NAZAR, M; SERRANO-NASCIMENTO, C; GOULART-SILVA, F; SOBRERO, G; TESTA, G; NUNEZ, MT; MUÑOZ, L; MIRAS, M; MASINI-REPISO, AM

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2011 vol. 96 p. 1100 - 1107

0021-972X

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: To perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical phenotype of ITD. Design: The genomic DNA encoding NIS was sequenced, and 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’-unstranslated 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.