The sodium/iodide symporter mutant V270E causes stunted growth but no cognitive deficiency

NICOLA, JP; REYNA-NEYRA, A; SAENGER, P; RODRIGUEZ-BURITICA, DF; GAMEZ GODOY, JD; MUZUMDAR, R; AMZEL, LM; CARRASCO, N

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Lugar: Washington; Año: 2015 vol. 100 p. 1353 - 1361

0021-972X

Context. Iodide (I-), anessential constituent of the thyroid hormones, is actively accumulated in thethyroid by the Na+/I- symporter (NIS), a key plasmamembrane protein encoded by the slc5a5gene. Mutations in slc5a5 cause I-transport defects (ITDs), autosomal recessive disorders in which I-accumulation is totally or partially impaired, leading to congenitalhypothyroidism. The characterization of NIS mutants has yielded significantinsights into the molecular mechanism of NIS.Objective. To determinethe basis of a patient?s clinical ITD phenotype, we sequenced her slc5a5 gene. As we identified a newmutation in NIS (V270E), we extensively characterized it to determine themolecular requirements of NIS at position 270. Design.Genomic DNA waspurified and the slc5a5 sequence determined. Functional in vitro studies were performed to characterize the V270E NISmutant.Patient.The index patientwas diagnosed with hypothyroidism with minimal radioiodide uptake in a normallylocated, although enlarged, thyroid gland. Results.We identified a new NIS mutation: V270E.The patient had the compoundheterozygous NIS mutation R124H/V270E. R124H NIS has been characterizedpreviously. We show that V270E markedly reduces I- uptake via a pronounced (but not total) impairmentof the protein´s plasma membrane targeting. Remarkably, V270E isintrinsically active. Therefore, a negative charge at position 270 interfereswith NIS cell surface trafficking. Thepatient?s minimal I- uptake enabled sufficient thyroid hormonebiosynthesis to prevent cognitive impairment.Conclusions. A non-polar residue at position 270?which allmembers of the SLC5A family have?is required for NIS plasma membrane targeting.