Molecular Characterization of the NIS Gene

The molecular characterization of NIS was accomplished in 1996 when Dai and colleagues cloned the transporter3 from Xenopus laevis oocytes, using the complementary DNA (cDNA) libraries derived from FRTL-5 cells (functional rat thyroid-derived cell line). The cDNA encoding the human NIS (hNIS) gene was identified on the expectation that hNIS would be highly homologous to rat NIS.7 The hNIS gene is located on chromosome 19pl2-13.2. It comprises 1929 base pairs encoding a 643-amino acid glycoprotein with a molecular weight of 70 to 90 kd. The variable molecular weight depends on the level of glycosylation of the protein. The coding region of hNIS contains 15 exons and 14 introns and codes for a 3.9-kb messenger RNA (mRNA).8 NIS is a membrane protein with 13 transmembrane domains with an extracellular NH2 terminus and an intracellular COOH terminus (Fig. 37-2). The configuration of the NH2 and COOH termini have been confirmed by immunohistochemistry.9 There are three potential asparagine (ASN) glycosylation sites at positions 225, 485, and 497.10 However, glycosylation has not been shown to affect the functionality, targeting, or stability of the NIS protein.8 Findings derived from NIS mutations that cause congenital iodide transport deficiency (ITD) show that a spontaneous single amino acid substitution of proline (Pro) instead of threonine (Thr) at position 354 (T354P) is the cause of congenital lack of iodide transport in several patients.1113 This suggests that a hydroxyl group at the P carbon position (Thr-354) is essential for NIS function.14 In the same patients, a mutation from valine-59 to glutamate has also been discovered.15

Subsequent to the cloning of hNIS, cDNAs encoding NIS have also been isolated from two other species, pig15 and mouse.16 Mouse NIS16 and rat NIS3 contain 618 amino acid residues, whereas human NIS7 and pig NIS15 contain 643. A highly conserved homologue among all isolated NIS proteins exists.

Colloid

Colloid

Thyrocyle

Blood

FIGURE 37-1. Schematic representation of the iodide uptake and biosynthetic pathways of thyroid hormones in thyrocytes. Iodine is actively accumulated across the basolateral plasma membrane of the thyrocyte in a process catalyzed by the sodium-iodide symporter (NIS). This transport is driven by the Na+ gradient generated under adenosine triphosphate (ATP) hydrolysis by Na+,K+-ATPase. The iodide is passively translocated across the apical membrane of the thyrocyte by the pendrin (PDS) protein into the colloid, where it is used to iodinate thyroglobulin (Tg). Iodine organification is catalyzed by thyroid peroxidase (TPO) and requires H202. The iodi-nated Tg, containing thyroid hormones, is stored in the colloid. Thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are released from Tg and secreted in the blood. All steps in the thyroid hormone biosynthetic pathway are stimulated by thyroid-stimulating hormone (TSH). TSH-R = TSH receptor.

Thyrocyle

Blood

FIGURE 37-1. Schematic representation of the iodide uptake and biosynthetic pathways of thyroid hormones in thyrocytes. Iodine is actively accumulated across the basolateral plasma membrane of the thyrocyte in a process catalyzed by the sodium-iodide symporter (NIS). This transport is driven by the Na+ gradient generated under adenosine triphosphate (ATP) hydrolysis by Na+,K+-ATPase. The iodide is passively translocated across the apical membrane of the thyrocyte by the pendrin (PDS) protein into the colloid, where it is used to iodinate thyroglobulin (Tg). Iodine organification is catalyzed by thyroid peroxidase (TPO) and requires H202. The iodi-nated Tg, containing thyroid hormones, is stored in the colloid. Thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are released from Tg and secreted in the blood. All steps in the thyroid hormone biosynthetic pathway are stimulated by thyroid-stimulating hormone (TSH). TSH-R = TSH receptor.

NIS gene expression is high in thyroid, gastric, and lactat-ing mammary glands, and lower levels are present in other tissues including brain, small intestines, testes, skin, spleen, ovary, and prostate.16

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