A Novel Mutation in the Sodium/Iodide Symporter Carboxy-Terminus Uncovers a Critical Tryptophan-Acid Domain Required for Plasma Membrane Targeting

MARTÍN M; PEYRET V; SIGNORINO M; TESTA GM; MODENUTTI C; SOBRERO GM; MUÑOZ L; MARTÍ M; MASINI - REPISO AM; MIRAS MB; NICOLA JP

Rio de Janeiro

Congreso; XVI Latin American Thyroid Congress (LATS); 2017

Latin American Thyroid Society (LATS)

Introduction: Iodide transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroid follicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that results from inactivating mutations in the slc5a5gene?which encodes the sodium iodide symporter (NIS). The clinical and biochemical presentation of ITD include low to absent thyroid and salivary iodide accumulation and, if untreated, the patients develop a variable degree of hypothyroidism, goiter, and even mental retardation.Objectives:To determine if a pediatric patient with a clinical phenotype of ITD harbors an inactivating mutation in the slc5a5gene, and if so, to ascertain the molecular mechanisms of the effect of the mutation on the biogenesis and activity of NIS.Methods: The whole coding region of the slc5a5 was PCR-amplified and subjected to Sanger sequencing, andin silico computational andin vitro functional studies of a newly identified NIS mutation were performed.Results and conclusions: We report a novel homozygous missense and loss-of-function mutation in the slc5a5 gene as a cause of ITD in a pediatric patient with dyshormonogenic congenital hypothyroidism. The patient carries a G>A transition at position +1.682 in exon 14 resulting in a Gly to Glu substitution at residue 561 (G561E) not previously reported in public reference exome databases. We show that G561E markedly reduces iodide uptake when the protein is heterologously expressed in MDCK-II cells, because targeting of G561E NIS to the plasma membrane is severely impaired. Replacing G561 with Gln also resulted in severe intracellular retention, suggesting that a bulky side-chain rather than a negative charge at position 561 interferes with NIS cell surface trafficking. Bioinformatics and biochemical analysis indicates that G561E impair the recognition of an adjacent tryptophan-acid domain by the kinesin light chain 2, thus impairing mutant NIS exit from the endoplasmic reticulum and subsequent plasma membrane targeting.