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- Title
Sodium/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency.
- Authors
Nicola, Juan Pablo; Reyna-Neyra, Andrea; Saenger, Paul; Rodriguez-Buritica, David F; Gamez Godoy, José David; Muzumdar, Radhika; Amzel, L Mario; Carrasco, Nancy
- Abstract
<bold>Context: </bold>Iodide (I(-)), an essential constituent of the thyroid hormones, is actively accumulated in the thyroid by the Na(+)/I(-) symporter (NIS), a key plasma membrane protein encoded by the slc5a5 gene. Mutations in slc5a5 cause I(-) transport defects (ITDs), autosomal-recessive disorders in which I(-) accumulation is totally or partially impaired, leading to congenital hypothyroidism. The characterization of NIS mutants has yielded significant insights into the molecular mechanism of NIS.<bold>Objective: </bold>This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene.<bold>Design: </bold>Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant.<bold>Patient: </bold>The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland.<bold>Results: </bold>We identified a new NIS mutation: V270E. The patient had the compound heterozygous NIS mutation R124H/V270E. R124H NIS has been characterized previously. We show that V270E markedly reduces I(-) uptake via a pronounced (but not total) impairment of the protein's plasma membrane targeting. Remarkably, V270E is intrinsically active. Therefore, a negative charge at position 270 interferes with NIS cell surface trafficking. The patient's minimal I(-) uptake enabled sufficient thyroid hormone biosynthesis to prevent cognitive impairment.<bold>Conclusions: </bold>A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.
- Subjects
ALLELES; COGNITION disorders; CONGENITAL hypothyroidism; GROWTH disorders; GENETIC mutation; RESEARCH funding; PHENOTYPES; ION transport (Biology); SEQUENCE analysis
- Publication
Journal of Clinical Endocrinology & Metabolism, 2015, Vol 100, Issue 10, pE1353
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2015-1824