Database: OMIMEntry: 601413
LinkDB: 601413
MIM Entry: 601413
Title:
*601413 DEIODINASE, IODOTHYRONINE, TYPE II; DIO2
;;THYROXINE DEIODINASE, TYPE II; TXDI2;;
D2
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.
References:
1. Araki, O.; Murakami, M.; Morimura, T.; Kamiya, Y.; Hosoi, Y.; Kato,
Y.; Mori, M.: Assignment of type II iodothyronine deiodinase gene
(DIO2) to human chromosome band 14q24.2-q24.3 by in situ hybridization. Cytogene t.
Cell Genet. 84: 73-74, 1999.
2. Bartha, T.; Kim, S.-W.; Salvatore, D.; Gereben, B.; Tu, H. M.;
Harney, J. W.; Rudas, P.; Larsen, P. R.: Characterization of the
5-prime-flanking and 5-prime-untranslated regions of the cyclic adenosine
3-prime,5-prime-monophosphate-responsive human type 2 iodothyronine
deiodinase gene. Endocrinology 141: 229-237, 2000.
3. Buettner, C.; Harney, J. W.; Larsen, P. R.: The 3-prime-untranslated
region of human type 2 iodothyronine deiodinase mRNA contains a functional
selenocysteine insertion sequence element. J. Biol. Chem. 273: 33374-33378,
1998.
4. Campos-Barros, A.; Amma, L. L.; Faris, J. S.; Shailam, R.; Kelley,
M. W.; Forrest, D.: Type 2 iodothyronine deiodinase expression in
the cochlea before the onset of hearing. Proc. Nat. Acad. Sci. 97:
1287-1292, 2000.
5. Celi, F. S.; Canettieri, G.; Yarnall, D. P.; Burns, D. K.; Andreoli,
M.; Shuldiner, A. R.; Centanni, M.: Genomic characterization of the
coding region of the human type II 5-prime-deiodinase gene. Molec.
Cell. Endocr. 141: 49-52, 1998.
6. Croteau, W.; Davey, J. C.; Galton, V. A.; St. German, D. L.: Cloning
of the mammalian type II iodothyronine deiodinase: a selenoprotein
differentially expressed and regulated in human and rat brain and
other tissues. J. Clin. Invest. 98: 405-417, 1996.
7. Curcio, C.; Baqui, M. M. A.; Salvatore, D.; Rihn, B. H.; Mohr,
S.; Harney, J. W.; Larsen, P. R.; Bianco, A. C.: The human type 2
iodothyronine deiodinase is a selenoprotein highly expressed in a
mesothelioma cell line. J. Biol. Chem. 276: 30183-30187, 2001.
8. Gereben, B.; Salvatore, D.; Harney, J. W.; Tu, H. M.; Larsen, P.
R.: The human, but not rat, dio2 gene is stimulated by thyroid transcription
factor-1 (TTF-1). Molec. Endocr. 15: 112-124, 2001.
9. Ng, L.; Goodyear, R. J.; Woods, C. A.; Schneider, M. J.; Diamond,
E.; Richardson, G. P.; Kelley, M. W.; St. Germain, D. L.; Galton,
V. A.; Forrest, D.: Hearing loss and retarded cochlear development
in mice lacking type 2 iodothyronine deiodinase. Proc. Nat. Acad.
Sci. 101: 3474-3479, 2004.
10. Ohba, K.; Yoshioka, T.; Muraki, T.: Identification of two novel
splicing variants of human type II iodothyronine deiodinase mRNA. Molec.
Cell. Endocr. 172: 169-175, 2001.
11. Salvatore, D.; Tu, H.; Harney, J. W.; Larsen, P. R.: Type 2 iodothyronine
deiodinase is highly expressed in human thyroid. J. Clin. Invest. 98:
962-968, 1996.
12. Schneider, M. J.; Fiering, S. N.; Pallud, S. E.; Parlow, A. F.;
St. Germain, D. L.; Galton, V. A.: Targeted disruption of the type
2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary
resistance to T4. Molec. Endocr. 15: 2137-2148, 2001.
13. Watanabe, M.; Houten, S. M.; Mataki, C.; Christoffolete, M. A.;
Kim, B. W.; Sato, H.; Messaddeq, N.; Harney, J. W.; Ezaki, O.; Kodama,
T.; Schoonjans, K.; Bianco, A. C.; Auwerx, J.: Bile acids induce
energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:
484-489, 2006.
Contributors:
Ada Hamosh - updated: 8/1/2006
Patricia A. Hartz - updated: 12/6/2004
John A. Phillips, III - updated: 8/5/2002
John A. Phillips, III - updated: 8/3/2001
Victor A. McKusick - updated: 2/22/2000
Creation Date:
Victor A. McKusick: 9/5/1996
Edit Dates:
wwang: 03/12/2010
alopez: 8/3/2006
terry: 8/1/2006
mgross: 12/9/2004
mgross: 12/6/2004
tkritzer: 12/2/2004
terry: 11/3/2004
cwells: 8/5/2002
alopez: 8/3/2001
mcapotos: 3/15/2000
mcapotos: 3/13/2000
terry: 2/22/2000
terry: 6/4/1998
carol: 5/2/1998
alopez: 6/11/1997
jenny: 4/8/1997
mark: 10/16/1996
terry: 10/9/1996
mark: 9/6/1996
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