SLC5A5 (solute carrier family 5 (sodium iodide symporter), member 5)

Note	The SLC5A5 gene was first sequenced in 1996 from rat and subsequently human thyroid (Dai et al., 1996; Smanik et al., 1996) and the exon-intron organization characterized in 1997 (Smanik et al., 1997).
Description	15 exons, spanning 23202 bp.
Transcription	Transcription starts at -375 relative to the ATG site. The minimal promoter is localized to a region of 144 bp that includes a 90-bp stretch (-478 and -389 bp) with 73% identity to the rat NIS proximal promoter and containing a TATA- and a GC-box. The region between -596 and -415 is essential for full promoter activity in human thyroid cells. A human NIS gene 5' far-upstream enhancer (hNUE) (-9847 to -8968) confers thyroid-specific and TSH-cAMP responsive transcription and contains an essential Pax-8 binding site and a cAMP response element (CRE)-like sequence activated by a CRE modulator (CREM) (Taki et al., 2002; Fenton et al., 2008). RNA: 3576 bases, open reading frame: 1929 bp. No splice variants are reported.
Pseudogene	No pseudogenes have been identified.

Note	The protein encoded by the SLC5A5 gene is more commonly referred to in the scientific literature as the Sodium Iodide Symporter or NIS.
	The diagram has been drawn following UniProtKB/Swiss-Prot database prediction and maintaining approximate length proportions among extracellular and intracellular segments. Transmembrane segments are represented by green rectangles, N-glycosylation sites in yellow.
Description	NIS is a glycoprotein with 643 aa and predicted molecular weight 69k Da. It is composed of 13 transmembrane domains, an extracellular N-terminal, a cytosolic C-terminal and three N-linked glycosylation sites at positions 225, 485 and 497. NIS is phosphorylated in vivo, mostly at the level of serines.
Expression	NIS is highly expressed and is active in the thyroid, stomach, salivary glands and lactating mammary gland. Low levels of NIS have also been detected by immunohistochemistry and/or RT-PCR in other extrathyroidal tissues (small intestine, colon, rectum, pancreas, kidney, bile duct, lung, lacrimal gland, heart, placenta, testis, ovaries, prostate gland, adrenal gland, thymus and pituitary gland), but it is not clear to what extent it is active in these tissues.
Localisation	Cell membrane. NIS is located on the basolateral membrane of thyroid follicular cells, lactating mammary gland alveolar cells, salivary gland ductal epithelial cells and gastric mucin-secreting cells. In contrast, NIS is located on the apical membrane of placental trophoblasts and enterocytes. In the kidney, NIS has a diffuse cytoplasmic distribution in distal tubular cells, but is more prominent in the basolateral aspect of proximal tubular cells.
Function	NIS mediates the transport of iodide (I-) into cells; it cotransports Na+ and I- on a 2:1 basis, using the inwardly directed Na+ concentration gradient generated by the Na+-K+ ATPase to concentrate I- to 30-50 times the extracellular concentration. The major function of NIS is to concentrate I- in the thyroid for the synthesis of thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4). Iodine, a trace element obtained with the diet, is organified into the thyroid hormone precursor thyroglobulin by thyroid peroxidase in the presence of hydrogen peroxide. Thyroidal NIS is regulated by thyroid stimulating hormone (TSH) under control of the hypothalamic-pituitary axis. Low circulating levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which in turn stimulates the secretion of TSH from the anterior pituitary gland. TSH increases NIS expression resulting in enhanced I- uptake and thyroid hormone synthesis. In contrast, high levels of circulating T3 and T4 inhibit TSH production through a negative feedback loop reducing iodide uptake and thyroid hormone production. TSH regulates NIS transcription via a cAMP-dependent pathway requiring binding of transcription factors Pax-8 and CREM to the hNUE enhancer element. TSH also regulates NIS trafficking, promoting NIS targeting to the plasma membrane. Mammary gland NIS drives the secretion of I- into milk in fulfillment of the newborn's dietary requirement for iodine and is induced by lactogenic hormones (prolactin, oxytocin). Placental NIS may provide the fetus with the necessary I- to synthesize thyroid hormones. NIS function in other tissues is unclear. I- secretion may play a role in mucosal host defense through the formation of reactive metabolites of iodine with antimicrobial activity. A role for NIS in the transport of thiocyanate and nitrate across mucosal barriers has also been proposed, again resulting in the formation of antimicrobial molecules.
Homology	NIS belongs to the SLC superfamily of solute carriers. The SLC5 family has 12 members to date (SLC5A1-SLC5A12) and includes Na+-coupled cotransporters that rely on the Na+ electrochemical gradient to drive solute transport into cells. NIS (SLC5A) has the highest homology with SLC5A12 (48% identity) and SLC5A8 (46% identity), both of which are thought to be sodium/monocarboxylate transporters and SLC5A6 (42% identity), a sodium/multivitamin transporter.

	Localisation of NIS mutations identified in iodide transport defect (ITD) (in red) and thyroid follicular adenoma (in blue).
Germinal	Germinal NIS mutations cause Iodide Transport Defect (ITD), a rare form of dyshormogenic congenital hypothyroidism with autosomal recessive inheritance (OMIM 274400). Twelve loss-of-function mutations have been reported to date: V59E, G93R, R124H, ΔM143-Q323, Q267E, C272X, T354P, G395R, ΔA439-P443, frame-shift 515X, Y531X, G543E. Mutations reduce thyroidal iodide uptake as a result of impaired NIS expression, maturation, trafficking or transport activity.
Somatic	A loss-of-function deletion of exon 6 was identified in a single case of follicular thyroid adenoma (Liang et al., 2005). No other somatic mutations have been reported in association with cancer.

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