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Gene Review

DIO2  -  deiodinase, iodothyronine, type II

Homo sapiens

Synonyms: 5DII, D2, DIOII, ITDI2, SelY, ...
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Disease relevance of DIO2

  • We performed molecular scanning of the human type 2 deiodinase (DIO2) gene and evaluated a novel variant for associations with obesity and insulin resistance, assessing both the main effect and interaction with the Trp64Arg beta-3--adrenergic receptor (ADRB3) variant [1].
  • DIO1 and DIO2 were underexpressed in nearly all papillary thyroid carcinomas [2].
  • We conclude 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 [3].
  • D2 mRNA was especially high in thyroids from Graves' patients and in follicular adenomas [3].
  • D2-generated T3 production accounts for approximately 71% of the peripheral T3 production in hypothyroidism, but D1 for approximately 67% in thyrotoxic patients [4].

Psychiatry related information on DIO2

  • Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China [5].
  • This review considers the roles that the three deiodinases, types 1, 2 and 3 (D1, D2, and D3), play in regulating intracellular levels of TH during this critical period [6].
  • We investigated the striatal dopamine-2 (D2) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using 123I-iodobenzamide (IBZM) as tracer substance [7].
  • Finally, alcoholics with antisocial personality disorder differed significantly in their allele sharing from nonalcoholics for both D2 polymorphisms [8].
  • Increased prefrontal D2 protein in Tourette syndrome: a postmortem analysis of frontal cortex and striatum [9].

High impact information on DIO2

  • The type II iodothyronine deiodinase plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulating the responses to SNS [10].
  • Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2) [11].
  • Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus [11].
  • Highly conserved FGF-D2 and FGF-linker (between D2-D3) interfaces define a general binding site for all FGF-FGFR complexes [12].
  • These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production [13].

Chemical compound and disease context of DIO2


Biological context of DIO2


Anatomical context of DIO2

  • Thus, deubiquitination regulates the supply of active thyroid hormone to brown adipocytes and other D2-expressing cells [19].
  • D1 activity and mRNA were only found in HepG2 hepatocarcinoma cells, and D2 activity was observed in none of the cell lines [20].
  • During incubations of intact COS cells expressing wt D2, D2 A131C, or D2 A131S, addition of increasing amounts of unlabeled T(4) resulted in the saturation of [(125)I]T(4) deiodination, as reflected in a decrease of [(125)I]T(3) release into the medium [21].
  • At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes [22].
  • The ratio of T3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2) [4].

Associations of DIO2 with chemical compounds

  • The pro-hormone T4 (3,3',5,5'-triiodothyronine) is converted in the brain to its active form, T3, or its inactive metabolite, reverse T3, mainly by the action of deiodinase type 2 (DIO2) [5].
  • VDU1, but not VDU2, is markedly increased in brown adipocytes by norepinephrine or cold exposure, further amplifying the increase in D2 activity that results from catecholamine-stimulated de novo synthesis [19].
  • Substitution of cysteine for a conserved alanine residue in the catalytic center of type II iodothyronine deiodinase alters interaction with reducing cofactor [21].
  • We have investigated whether D2 mutants with a cysteine (A131C) or serine (A131S) two-residue amino terminal to the SeC are enzymatically active and have characterized these mutants with regard to substrate affinity, reducing cofactor interaction and inhibitor profile [21].
  • The wt and mutant D2 enzymes are essentially insensitive to propylthiouracil [concentration inhibiting 50% of activity (IC(50)) > 2 mM] in the presence of 20 mM DTT, but when tested in the presence of 0.2 mM DTT the IC(50) value for propylthiouracil is reduced to about 0.1 mM [21].

Physical interactions of DIO2

  • The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors [22].

Regulatory relationships of DIO2

  • In conclusion, Ubc6p and Ubc7p are required for normal and substrate-induced ubiquitination and proteolysis of D2 [23].
  • Some researchers formulated the hypothesis that TSH receptor expression in the brain may be involved in local thyroid homeostasis through TSH stimulating the DIO2 activity [24].

Other interactions of DIO2

  • Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 plus minus 0.9 kg/m(2) vs. neither variant 33.1 plus minus 0.4 kg/m(2), P = 0.04 for interaction) [1].
  • The rank order of preference (Ki ratio, D2:D3) for D3 receptors (labeled by [3H]-PD 128,907) vs. D2 sites (labeled by [125I]-iodosulpride) was (+)-S 14297 (61) approximately GR 103,691 (60) > U 99194 (14) > nafadotride (9) approximately (+)-UH 232 (8) approximately (+)-AJ 76 (6) > haloperidol (0.2) [25].
  • The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop in D2 that confers metabolic instability, whereas the SOCS-box domain mediates its interaction with a ubiquitinating catalytic core complex, modelled as Elongin BC-Cul5-Rbx1 (ECS(WSB-1)) [26].
  • These findings suggest that the prohormone thyroxine (T4) is taken up in hypothalamic glial cells that convert T4 into the biologically active triiodothyronine (T3) via the enzyme D2, and that T3 is subsequently transported to TRH producing neurons in the PVN [27].
  • The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2 [28].

Analytical, diagnostic and therapeutic context of DIO2


  1. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Mentuccia, D., Proietti-Pannunzi, L., Tanner, K., Bacci, V., Pollin, T.I., Poehlman, E.T., Shuldiner, A.R., Celi, F.S. Diabetes (2002) [Pubmed]
  2. Gene expression profiles reveal that DCN, DIO1, and DIO2 are underexpressed in benign and malignant thyroid tumors. Arnaldi, L.A., Borra, R.C., Maciel, R.M., Cerutti, J.M. Thyroid (2005) [Pubmed]
  3. Type 2 iodothyronine deiodinase is highly expressed in human thyroid. Salvatore, D., Tu, H., Harney, J.W., Larsen, P.R. J. Clin. Invest. (1996) [Pubmed]
  4. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Maia, A.L., Kim, B.W., Huang, S.A., Harney, J.W., Larsen, P.R. J. Clin. Invest. (2005) [Pubmed]
  5. Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China. Guo, T.W., Zhang, F.C., Yang, M.S., Gao, X.C., Bian, L., Duan, S.W., Zheng, Z.J., Gao, J.J., Wang, H., Li, R.L., Feng, G.Y., St Clair, D., He, L. J. Med. Genet. (2004) [Pubmed]
  6. The roles of the iodothyronine deiodinases in mammalian development. Galton, V.A. Thyroid (2005) [Pubmed]
  7. IBZM SPECT imaging of striatal dopamine-2 receptors in psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol. Küfferle, B., Tauscher, J., Asenbaum, S., Vesely, C., Podreka, I., Brücke, T., Kasper, S. Psychopharmacology (Berl.) (1997) [Pubmed]
  8. Linkage studies of D2 and D4 receptor genes and alcoholism. Hill, S.Y., Zezza, N., Wipprecht, G., Xu, J., Neiswanger, K. Am. J. Med. Genet. (1999) [Pubmed]
  9. Increased prefrontal D2 protein in Tourette syndrome: a postmortem analysis of frontal cortex and striatum. Minzer, K., Lee, O., Hong, J.J., Singer, H.S. J. Neurol. Sci. (2004) [Pubmed]
  10. Thermogenic mechanisms and their hormonal regulation. Silva, J.E. Physiol. Rev. (2006) [Pubmed]
  11. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Dumitrescu, A.M., Liao, X.H., Abdullah, M.S., Lado-Abeal, J., Majed, F.A., Moeller, L.C., Boran, G., Schomburg, L., Weiss, R.E., Refetoff, S. Nat. Genet. (2005) [Pubmed]
  12. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Plotnikov, A.N., Hubbard, S.R., Schlessinger, J., Mohammadi, M. Cell (2000) [Pubmed]
  13. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Bianco, A.C., Salvatore, D., Gereben, B., Berry, M.J., Larsen, P.R. Endocr. Rev. (2002) [Pubmed]
  14. Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Trivieri, M.G., Oudit, G.Y., Sah, R., Kerfant, B.G., Sun, H., O Gramolini, A., Pan, Y., Wickenden, A.D., Croteau, W., Morreale de Escobar, G., Pekhletski, R., St Germain, D., Maclennan, D.H., Backx, P.H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  15. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. Curcio, C., Baqui, M.M., Salvatore, D., Rihn, B.H., Mohr, S., Harney, J.W., Larsen, P.R., Bianco, A.C. J. Biol. Chem. (2001) [Pubmed]
  16. Chronic cardiac-specific thyrotoxicosis increases myocardial beta-adrenergic responsiveness. Carvalho-Bianco, S.D., Kim, B.W., Zhang, J.X., Harney, J.W., Ribeiro, R.S., Gereben, B., Bianco, A.C., Mende, U., Larsen, P.R. Mol. Endocrinol. (2004) [Pubmed]
  17. Assignment of type II iodothyronine deiodinase gene (DIO2) to human chromosome band 14q24.2-->q24.3 by in situ hybridization. Araki, O., Murakami, M., Morimura, T., Kamiya, Y., Hosoi, Y., Kato, Y., Mori, M. Cytogenet. Cell Genet. (1999) [Pubmed]
  18. Triplets! Unexpected structural similarity among the three enzymes that catalyze initiation and termination of thyroid hormone effects. Bianco, A.C. Arquivos brasileiros de endocrinologia e metabologia. (2004) [Pubmed]
  19. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. Curcio-Morelli, C., Zavacki, A.M., Christofollete, M., Gereben, B., de Freitas, B.C., Harney, J.W., Li, Z., Wu, G., Bianco, A.C. J. Clin. Invest. (2003) [Pubmed]
  20. Regulation of Type III Iodothyronine Deiodinase Expression in Human Cell Lines. Kester, M.H., Kuiper, G.G., Versteeg, R., Visser, T.J. Endocrinology (2006) [Pubmed]
  21. Substitution of cysteine for a conserved alanine residue in the catalytic center of type II iodothyronine deiodinase alters interaction with reducing cofactor. Kuiper, G.G., Klootwijk, W., Visser, T.J. Endocrinology (2002) [Pubmed]
  22. Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra. Newman-Tancredi, A., Cussac, D., Brocco, M., Rivet, J.M., Chaput, C., Touzard, M., Pasteau, V., Millan, M.J. Brain Res. (2001) [Pubmed]
  23. Ubc6p and ubc7p are required for normal and substrate-induced endoplasmic reticulum-associated degradation of the human selenoprotein type 2 iodothyronine monodeiodinase. Botero, D., Gereben, B., Goncalves, C., De Jesus, L.A., Harney, J.W., Bianco, A.C. Mol. Endocrinol. (2002) [Pubmed]
  24. Polymorphisms in the TSHR (thyrotropin receptor) gene on chromosome 14q31 are not associated with mental retardation in the iodine-deficient areas of China. Guo, T.W., Zhang, F.C., Gao, J.J., Bian, L., Gao, X.C., Ma, J., Yang, M., Ji, Q., Duan, S.W., Zheng, Z.J., Li, R.L., Feng, G.Y., St Clair, D., He, L. Neurosci. Lett. (2005) [Pubmed]
  25. A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194. Audinot, V., Newman-Tancredi, A., Gobert, A., Rivet, J.M., Brocco, M., Lejeune, F., Gluck, L., Desposte, I., Bervoets, K., Dekeyne, A., Millan, M.J. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  26. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Dentice, M., Bandyopadhyay, A., Gereben, B., Callebaut, I., Christoffolete, M.A., Kim, B.W., Nissim, S., Mornon, J.P., Zavacki, A.M., Zeöld, A., Capelo, L.P., Curcio-Morelli, C., Ribeiro, R., Harney, J.W., Tabin, C.J., Bianco, A.C. Nat. Cell Biol. (2005) [Pubmed]
  27. Functional neuroanatomy of thyroid hormone feedback in the human hypothalamus and pituitary gland. Fliers, E., Unmehopa, U.A., Alkemade, A. Mol. Cell. Endocrinol. (2006) [Pubmed]
  28. Endoplasmic reticulum-associated degradation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2. Kim, B.W., Zavacki, A.M., Curcio-Morelli, C., Dentice, M., Harney, J.W., Larsen, P.R., Bianco, A.C. Mol. Endocrinol. (2003) [Pubmed]
  29. Characterization of the 5'-flanking and 5'-untranslated regions of the cyclic adenosine 3',5'-monophosphate-responsive human type 2 iodothyronine deiodinase gene. Bartha, T., Kim, S.W., Salvatore, D., Gereben, B., Tu, H.M., Harney, J.W., Rudas, P., Larsen, P.R. Endocrinology (2000) [Pubmed]
  30. Functional characterisation of the CRE/TATA box unit of type 2 deiodinase gene promoter in a human choriocarcinoma cell line. Canettieri, G., Franchi, A., Sibilla, R., Guzmán, E., Centanni, M. J. Mol. Endocrinol. (2004) [Pubmed]
  31. The Thr92Ala deiodinase type 2 (DIO2) variant is not associated with type 2 diabetes or indices of insulin resistance in the old order of Amish. Mentuccia, D., Thomas, M.J., Coppotelli, G., Reinhart, L.J., Mitchell, B.D., Shuldiner, A.R., Celi, F.S. Thyroid (2005) [Pubmed]
  32. Somatosensory cortical plasticity in carpal tunnel syndrome--a cross-sectional fMRI evaluation. Napadow, V., Kettner, N., Ryan, A., Kwong, K.K., Audette, J., Hui, K.K. Neuroimage (2006) [Pubmed]
  33. D2-like dopamine receptors are not detectable on human peripheral blood lymphocytes. Vile, J.M., Strange, P.G. Biol. Psychiatry (1996) [Pubmed]
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