TY - JOUR
T1 - Sodium/iodide symporter mutant V270E causes stunted growth but no cognitive deficiency
AU - Nicola, Juan Pablo
AU - Reyna-Neyra, Andrea
AU - Saenger, Paul
AU - Rodriguez-Buritica, David F.
AU - Godoy, José David Gamez
AU - Muzumdar, Radhika
AU - Amzel, L. Mario
AU - Carrasco, Nancy
N1 - Publisher Copyright:
Copyright © 2015 by the Endocrine Society.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Context: 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. Objective: This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene. Design: Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant. Patient: The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland. Results: 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. Conclusions: A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.
AB - Context: 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. Objective: This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene. Design: Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant. Patient: The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland. Results: 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. Conclusions: A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.
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U2 - 10.1210/jc.2015-1824
DO - 10.1210/jc.2015-1824
M3 - Article
C2 - 26204134
AN - SCOPUS:84943757131
SN - 0021-972X
VL - 100
SP - E1353-E1361
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -