Table of Contents - *601413
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Genome
DNA
Protein
Gene Info
Variation
Animal Models
Cellular Pathways
| *601413 | |||||||||||||||||||||||||||||||||||||||
| DEIODINASE, IODOTHYRONINE, TYPE II; DIO2 | |||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||
| THYROXINE DEIODINASE, TYPE II; TXDI2 D2 | |||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: DIO2 | |||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 14q31.1 Genomic coordinates (GRCh37): 14:80,663,867 - 80,697,396 (from NCBI) | |||||||||||||||||||||||||||||||||||||||
| TEXT | |||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||
| Type II iodothyronine deiodinase is a selenoprotein that catalyzes the 5-prime deiodination of thyroxine (T4) to generate an active thyroid hormone, 3,3-prime,5-triiodothyronine (T3) (Ohba et al., 2001). | |||||||||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||||||||
| Croteau et al. (1996) identified and characterized rat and human DII cDNAs. Both code for selenoproteins and exhibit limited regions of homology with DI (DIO1; 147892) and DIII (DIO3; 601038). In the rat pituitary and brown adipose tissue, DII mRNA levels are altered more than 10-fold by changes in the thyroid hormone status of the animal. Northern analysis of RNA derived from human tissues revealed expression of DII transcripts in heart, skeletal muscle, placenta, fetal brain, and several regions of the adult brain. By EST database analysis, followed by 3-prime RACE of total thyroid RNA, Buettner et al. (1998) extended the DIO2 sequence isolated by Croteau et al. (1996) in the 3-prime direction and cloned full-length DIO2. The 3-prime sequence contains several AU-rich elements. Just upstream of the polyadenylation signal in the 3-prime UTR is a predicted stem loop structure with features of a form-2 selenocysteine insertion sequence (SECIS), which is required to decode a UGA codon as selenocysteine. Northern blot analysis of thyroid mRNA detected transcripts of about 6.5 and 7.5 kb. EST database analysis identified DIO2 clones from thyroid, brain, retina, placenta, breast, uterus, prostate, and skin libraries. In addition, DIO2 clones were found in several libraries derived from pooled tissues, such as fetal liver and spleen or fetal testis, B cell, and lung. Using Northern blot analysis, Bartha et al. (2000) detected DIO2 transcripts of about 6.8 and 7.5 kb in thyroid, pituitary, cardiac and skeletal muscle, and possibly brain, but only a 7.5-kb transcript was detected in placenta. PCR and endonuclease digestion indicated that there are 4 primary transcripts in thyroid: the full-length 7.5-kb transcript, a 7.2-kb transcript, and 2 shorter transcripts that use alternate start sites just upstream of the ATG start codon. By PCR, Ohba et al. (2001) identified 2 alternatively spliced DIO2 transcripts that include intronic sequences between the 2 invariant DIO2 exons. These splice variants showed tissue-specific expression. By SDS-PAGE of mesothelioma cell lysates, Curcio et al. (2001) determined that endogenous DIO2 has an apparent molecular mass of 31 kD. Immunolocalization of DIO2 in this cell line showed DIO2 costaining with an endoplasmic reticulum resident protein. | |||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||
| Croteau et al. (1996) noted that thyroid hormone appears to have important regulatory effects in some mammalian tissues, such as the developing brain, the anterior pituitary gland, and brown adipose tissue. A relatively high proportion of the receptor-bound triiodothyronine is found within the tissue itself rather than in plasma. The expression in these tissues of type II iodothyronine deiodinase (symbolized DII by them), which catalyzes deiodination of thyroxine T4 exclusively on the outer ring (5-prime-position) to yield T3, suggests that DII is responsible for this 'local' production of T3 and is thus important in influencing thyroid hormone action in these tissues. In addition, DII activity is markedly elevated in the hypothyroid state and appears to be responsible for catalyzing the production of a large proportion of the circulating T3 under such conditions. Croteau et al. (1996) noted that, from the cDNAs of iodothyronine deiodinase types I and III, deiodinases are known to contain in-frame TGATGA codons that code for selenocysteine. The catalytic properties and tissue patterns of expression of these selenoproteins differ from those of DII. Unlike DII, DI is expressed in liver and kidney and is capable of inner ring deiodination of sulfated thyroid hormone conjugates. DIII functions as an inner ring deiodinase to convert T4 and T3 to inactive metabolites. Its expression in placenta and several fetal tissues during early development suggested that it plays a role in preventing premature exposure of developing tissues to adult levels of thyroid hormones. DII also is present in several fetal and neonatal tissues and is essential for providing the brain with appropriate levels of T3 during the critical period of development. Salvatore et al. (1996) reported that type 2 iodothyronine deiodinase (referred to as D2 by them) is highly expressed in human thyroid at levels 50- to 150-fold higher than in placenta. D2 mRNA was especially high in thyroids from Graves patients and in follicular adenomas. Stimulated thyroids had higher D2 to D1 (i.e., TXDI1) mRNA ratios than normal or multinodular glands, suggesting differential regulation of D1 and D2 expression. They concluded that intrathyroidal T4-to-T3 conversion by D2 may contribute significantly to the relative increase in thyroidal T3 production in patients with Graves disease, toxic adenomas, and, perhaps, iodine deficiency. Buettner et al. (1998) confirmed that the SECIS element in the 3-prime UTR of DIO2 has SECIS activity. A fragment containing the stem loop structure and the SECIS element hybridized to DIO2 mRNA in human thyroid. A G-to-A mutation in the essential AUGA motif in the SECIS element abolished SECIS activity. Transfection of the DIO2 coding region plus the 3-prime UTR in human embryonic kidney cells or injection of DIO2 cRNA in Xenopus oocytes resulted in expression of DIO2 with deiodinase activity. The distance between the SECIS element and the UGA codon affected DIO2 activity. Bartha et al. (2000) identified a canonical cAMP response element (CRE) in the DIO2 promoter region that drove cAMP-dependent expression of a reporter gene. Primary human thyroid cell cultures increased basal expression of DIO2 in response to forskolin, confirming the cAMP responsiveness of the endogenous DIO2 gene. Curcio et al. (2001) found that selenium depletion reduced the basal endogenous DIO2 activity in a mesothelioma cell line. This depletion could be reversed by selenium supplementation in a dose- and time-dependent fashion. DIO2 activity also increased following exposure to a nonhydrolyzable cAMP analog. Exposure to the thyroxine substrate increased the degradation of DIO2, resulting in decreased DIO2 activity. The short half-life of endogenous DIO2 (less than 1 hr) and the increased degradation of DIO2 in the presence of thyroxine were reduced or eliminated by exposure to proteasome inhibitors. Thyroid hormone signaling during a postnatal period in the mouse is essential for cochlear development and the subsequent onset of hearing. To study the control of this temporal dependency, Campos-Barros et al. (2000) investigated the role of iodothyronine deiodinases, which in target tissues convert the prohormone thyroxine into T3, the active ligand for the thyroid hormone receptor (see 190120). They found that D2 activity rose dramatically in the mouse cochlea to peak around postnatal day 7 (P7), after which activity declined by P10. This activity peaked a few days before the onset of hearing, suggesting a role for D2 in amplifying local T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA was isolated and shown to have near identity to rat D2. In situ hybridization localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear outer capsule, and the septal divisions between the turns of the cochlea. D2 expression in these regions that give rise to the bony labyrinth was complementary to thyroid hormone receptor expression in the sensory epithelium. Thus, the connective tissue may control deiodination of thyroxine and release of T3 to confer a paracrine-like control of thyroid hormone receptor activation. These results suggested that temporal and spatial control of ligand availability conferred by D2 provides an important level of regulation of the thyroid hormone receptor pathways required for cochlear maturation. DIO2 mRNA is abundant in the human thyroid but very low in adult rat thyroid, whereas DIO1 activity is high in both. To understand the molecular regulation of these genes in thyroid cells, Gereben et al. (2001) studied the effect of TITF1 (NKX2-1; 600635) and PAX8 (167415) on the transcriptional activity of the deiodinase promoters. Both the approximately 6.5-kb human DIO2 sequence and its most 3-prime 633 bp were activated 10-fold by transiently expressed TITF1 in COS-7 cells, but human DIO1 was unaffected. Surprisingly, the response of the rat DIO2 gene to TITF1 was only 3-fold despite the 73% identity with the proximal 633-bp region of human DIO2, including complete conservation of a functional cAMP response element at -90. Neither human nor rat DIO2 nor human DIO1 was induced by PAX8. Two sites in human DIO2, both of which are absent in rat DIO2, have significant affinity for, and are required for the full response to, TITF1. Watanabe et al. (2006) showed that the administration of bile acids to mice increased energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of bile acids is critically dependent on the induction of the cAMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2), shown by the loss of this effect in D2-null mice. Treatment of brown adipocytes and human skeletal myocytes with bile acids increased D2 activity and oxygen consumption. These effects are independent of FXR-alpha (see 603826), and instead are mediated by increased cAMP production that stems from the binding of bile acids with the G protein-coupled receptor TGR5 (610147). In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism since they coexpress D2 and TGR5. Watanabe et al. (2006) concluded that the bile acid-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control. | |||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||
| Celi et al. (1998) determined that the coding region of the DIO2 gene covers 8.1 kb and contains 2 exons separated by a long intron. Bartha et al. (2000) determined that the 5-prime UTR of the DIO2 gene contains a functional CRE. It also has an AP1 (165160) site, several TATA or TATA-like sequences, and 3 transcriptional start sites. Bartha et al. (2000) identified a DIO2 splice variant that uses intronic sequences in addition to the 2 exons described by Celi et al. (1998). Ohba et al. (2001) determined that the long intronic sequence of the DIO2 gene contains 2 alternatively spliced sequences used by some DIO2 splice variants. | |||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||
| By radiation hybrid analysis, Celi et al. (1998) mapped the DIO2 gene to chromosome 14q24.3. Using FISH, Araki et al. (1999) mapped the DIO2 gene to chromosome 14q24.2-q24.3. | |||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||
| DIO2 is a selenoenzyme that catalyzes the conversion of T4 to T3 via 5-prime-deiodination. It is expressed in the pituitary, brain, brown adipose tissue, and the reproductive tract. To examine the physiologic role of DIO2, Schneider et al. (2001) developed a mouse strain lacking Dio2 activity. Mice homologous for the targeted deletion (Dio2 knockout mice) had no gross phenotypic abnormalities, and development and reproductive function appeared normal, except for mild growth retardation (9%) in males. Serum T4 and TSH levels were both elevated significantly (40% and 100%, respectively) in the Dio2 knockout mice, suggesting that the pituitary gland is resistant to the feedback effect of plasma T4. This was supported by finding that serum TSH levels in hypothyroid wildtype mice were suppressed by administration of either T4 or T3, but only T3 was effective in the Dio2 mouse. Ng et al. (2004) found that D2-deficient mice had defective auditory function, retarded differentiation of the cochlear inner sulcus and sensory epithelium, and deformity of the tectorial membrane. They concluded that the similarity of the D2-deficient phenotype to that caused by deletion of thyroid hormone receptor genes suggests that D2 is essential for hearing and that D2 confers on the cochlea the ability to stimulate its own T3 response at a critical developmental period. | |||||||||||||||||||||||||||||||||||||||
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