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Submitted on August 12, 2005
Accepted on January 9, 2006
Pediatric Endocrine Unit, and INSERM EMI 0363, Hôpital Necker, Enfants-Malades, Paris, France; Department of Clinical Genetics and Department of Medical Ethics, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Endocrinology and Diabetes, Molecular Laboratory, CHU, Rennes, France; Pediatric Endocrine and Diabetes Unit, Hôpital Robert Debré, Paris, France
* To whom correspondence should be addressed. E-mail: michel.polak{at}nck.ap-hop-paris.fr.
Context. Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter, 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: 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.
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 in the neonatal period with four NIS mutations (NOH genotype), during infancy with 3 NIS mutations (IOH genotype), and during childhood with 3 NIS mutations (COH genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the NOH genotype (0.88% ± 0.2) than the IOH (1.9% ± 0.4, P < 0.05) and COH (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.
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