Extending the clinical heterogeneity of iodide transport defect (ITD): A novel mutation R124H of the sodium/iodide symporter gene and review of genotype-phenotype correlations in ITD

Context: Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter and low or absent radioiodide uptake (RIUT), as determined by thyroid scintigraphy, and low iodide saliva to plasma ratio. Defects of the sodium/iodide symporter gene (NIS) have been shown to cause ITD. Objective: We describe molecular studies of NIS in a patient with ITD and genotype-phenotype correlation analysis in 31 patients with NIS defects reported worldwide. Design: NIS sequencing and functional studies of the new NIS mutation in vitro were performed. Results: In a newborn with symptomatic CH and a large goiter, thyroid scintigraphy showed no RIUT (0%). NIS sequencing identified the new homozygous mutation, R124H, in exon 2. This mutation was associated with abolition of iodide uptake in vitro when transfected in COS-7 cells. Immunocytochemical studies documented correct targeting of the mutated protein to the plasma membrane of transfected cells. Genotype-phenotype correlation analysis showed that the onset of hypothyroidism occurred during the neonatal period with four NIS mutations (neonatal onset of hypothyroidism genotype), during infancy with three NIS mutations (infancy onset of hypothyroidism genotype), and during childhood with three NIS mutations (childhood onset of hypothyroidism genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the neonatal onset of hypothyroidism genotype (0.88 +/- 0.2%) than in the infancy onset of hypothyroidism (1.9 +/- 0.4%; P < 0.05) and childhood onset of hypothyroidism (2.6 +/- 0.7%; P < 0.05) genotypes. Conclusions: We identified a new NIS mutation, R124H, in a newborn with the complete clinical ITD phenotype. Genotype-phenotype correlations suggest that age at hypothyroidism onset may be genotype specific and may depend on genotype-specific residual NIS activity.