Database: OMIMEntry: 147892
LinkDB: 147892
MIM Entry: 147892
Title:
+147892 DEIODINASE, IODOTHYRONINE, TYPE I; DIO1
;;THYROXINE DEIODINASE, TYPE I; TXDI1
HYPERTHYROXINEMIA DUE TO DECREASED PERIPHERAL CONVERSION OF T4, INCLUDED;;
5-PRIME-@DEIODINASE DEFICIENCY, GENERALIZED, CAUSING EUTHYROID HYPERTHYROXINEMIA ,
INCLUDED
Text:
Although thyroxine (tetraiodothyronine; T4) is the principal secretory
product of the vertebrate thyroid, its essential metabolic and
developmental effects are all mediated by triiodothyronine (T3), which
is produced from the prohormone by 5-prime-deiodination. The type I
iodothyronine deiodinase, a thiol-requiring propylthiouracil-sensitive
oxidoreductase, is found mainly in liver and kidney. Using expression
cloning in the Xenopus oocyte, Berry et al. (1991) isolated a 2.1-kb
cDNA for this deiodinase from a rat liver cDNA library. Its authenticity
was confirmed by the kinetic properties of the protein expressed in
transient assay systems, the tissue distribution of the mRNA, and its
changes with thyroid status. Berry et al. (1991) found that the mRNA for
iodothyronine deiodinase contains a UGA codon for selenocysteine which
is necessary for maximal enzyme activity. The finding explains why
conversion of T4 to T3 is impaired in experimental selenium deficiency
and identifies an essential role for this trace element in thyroid
hormone action. Previously the only enzyme known to contain a
selenocysteine was glutathione peroxidase (138320). There is no apparent
homology otherwise between the sequences of the 2 genes.
Mandel et al. (1992) cloned a human iodothyronine deiodinase gene
(designated 5-prime DI, or 5DI, by them) from liver and kidney cDNA
libraries. The predicted protein has a molecular mass of 28.7 kD and
contains a selenocysteine at position 382. The human gene is 88% similar
to the rat homolog. The gene is also symbolized TXDI1 for thyroxine
deiodinase type I. See also TXDI3 (601038) and TXDI2 (601413).
Hatfield and Diamond (1993) pointed out that of all the genetic code
words, UGA has played the largest number of distinct roles in evolution.
In today's genetic language, UGA serves as a termination codon in the
universal genetic code, a tryptophan codon in mitochondria and
mycoplasma, and a selenocysteine codon in E. coli and in mammals.
Indeed, UGA codes for selenocysteine in representatives of all the life
kingdoms: monera, protist, plant, animal, and fungi. AUG has long been
known to serve a dual role in the universal genetic code; it codes for
the initiation of protein synthesis and, at internal positions of
protein, for methionine.
By FISH, Jakobs et al. (1997) mapped the human DIO1 gene to chromosome
1p33-p32.
Jansen et al. (1982) described 2 patients, an 8-year-old boy and a
60-year-old woman, with elevated levels of serum thyroxine but normal
serum triiodothyronine. The pituitary-thyroid axis could be normally
stimulated by thyrotropin-releasing hormone. High levels of serum
T4-binding globulin decreased during T3 treatment in the boy. In these
patients, raised serum T4 was necessary to produce in the peripheral
tissues sufficient T3 to maintain the euthyroid state. The authors
suggested that the defect resides either in the transport of T4 into
tissue cells or in 5-prime-deiodinase activity catalyzing the T4 to T3
conversion. Studies of the families showed no clue as to whether the
disorder was hereditary. The boy was ascertained because of
constitutional delay and problems in infancy related perhaps to toxemia
of pregnancy and umbilical cord strangulation and amniotic fluid
aspiration at birth. The woman had undergone subtotal thyroidectomy for
Graves disease.
Kleinhaus et al. (1988) described an 11-year-old girl with asymptomatic
hyperthyroxinemia who remained euthyroid and healthy during 5 years of
observation. Besides having elevated serum T4 concentrations, she showed
low-normal or definitely low levels of deiodinated forms of T4. The girl
had a small diffuse goiter, her serum TSH (see 188540) response to TRH
was exaggerated, and thyroid radioiodine was elevated, suggesting
slightly increased TSH secretion and, consequently, increased thyroid
secretion. Kleinhaus et al. (1988) interpreted the findings as
indicating reduced activity of several, and perhaps all, peripheral
5-prime-deiodination pathways, including possibly also thyrotroph T4
5-prime-deiodination. Thus, the girl appeared to have a previously
unrecognized syndrome of generalized 5-prime-deiodinase deficiency. The
genetic nature of the abnormality could not be determined; all
relatives, including the parents and 4 sibs, had normal serum T4 levels
and were healthy.
Inbred mouse strains differ in their capacity to deiodinate iododioxin
and iodothyronines, with strains segregating into high or low activity
groups. Metabolism of iododioxin occurs via the type I iodothyronine
5-prime deiodinase. Berry et al. (1993) found that recombinant inbred
strains derived from crosses between high and low activity strains
exhibited segregation characteristic of a single allele difference.
Linkage was performed using a restriction fragment length variant from
the deiodinase gene. Linkage with previously mapped loci allowed
assignment of the gene to mouse chromosome 4 in a region that shows
extensive homology of synteny with the short arm of chromosome 1. Maia
et al. (1995) identified an abnormality of the dio1 gene in mice with
inherited deficiency of type 1 deiodinase.
Toyoda et al. (1996) analyzed the exon/intron structure of the human
DIO1 gene and compared it with that of a patient with suspected
congenital type I deiodinase deficiency. The human gene is identical in
exon/intron arrangement to the mouse gene, with coding sequences and a
selenocysteine insertion sequence element contained in 4 exons. There
were no mutations in the sequences of exons 1-4 of the patient's genomic
DNA. Functional studies by transient expression techniques showed no
difference in basal promoter activity or T3 responsiveness between the
patient's and the normal gene. Thus, Toyoda et al. (1996) concluded that
a structural abnormality in the type I iodothyronine deiodinase gene is
not a likely explanation for this patient's deiodinase-deficient
phenotype.
Peeters et al. (2003) investigated the occurrence and possible effects
of SNPs in the deiodinases (DIO1; DIO2, 601413; DIO3, 601038), the TSH
receptor (TSHR; 603372), and the thyroid hormone receptor-beta (THRB;
190160) genes. They identified 8 SNPs of interest, 4 of which had not
yet been published. Three are located in the 3-prime untranslated
region: a C/T variation at nucleotide position 785 of the DIO1 cDNA,
referred to as D1a-C/T (allele frequencies, C = 66%, T = 34%); an A/G
variation at position 1814, referred to as D1b-A/G (A = 89.7= %, G =
10.3%); and a T/G polymorphism at nucleotide position 1546 of the DIO3
cDNA, referred to as D3-T/G (T = 85.5%, G = 14.2%). D1a-T was associated
in a dose-dependent manner with a higher plasma reverse T3 (rT3), a
higher plasma rT3/T4, and a lower T3/rT3 ratio. The D1b-G allele was
associated with lower plasma rT3/T4 and with higher T3/rT3 ratios. The G
allele of the TSHRc-C/G (asp727 to glu) polymorphism, TSHRc-G, was
associated with a lower plasma TSH and with lower plasma TSH/free T4,
TSH/T3, and TSH/T4 ratios. The authors concluded that they found
significant associations of 3 SNPs in 2 genes (DIO1, TSHR) with plasma
TSH or iodothyronine levels in a normal population.
De Jong et al. (2007) studied the association of polymorphisms in the
DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes
with circulating thyroid parameters and early neuroimaging markers of
Alzheimer disease (AD; see 104300). Carriers of the D1a-T allele had
higher serum free T4 and reverse rT3, lower T3, and lower T3/rT3. The
D1b-G allele was associated with higher serum T3 and T3/rT3. They
concluded that there is an association of D1a-C/T and D1b-A/G
polymorphisms with iodothyronine levels in the elderly, and that
polymorphisms in the DIO1 and DIO2 genes are not associated with early
MRI markers of AD.
Peeters et al. (2005) investigated whether genetic variations in DIO1
are associated with the insulin-like growth factor-1 (IGF1; 147440)
system. In 156 blood donors and 350 elderly men, the association of DIO1
haplotype alleles with circulating IGF1 and free IGF1 levels was
studied. In addition, they investigated potential associations with
muscle strength and body composition in the elderly population. Finally
the relation between serum iodothyronine levels and IGF1 levels was
studied. In blood donors, haplotype allele 2 (D1a-T/D1b-A) was
associated with higher levels of free IGF1. In elderly men, haplotype
allele 2 also showed an allele dose increase in free IGF1 levels and an
allele dose decrease in serum triiodothyronine (T3) levels, independent
of age. In blood donors, tetraiodothyronine (T4) and free T4 were
negatively correlated with total IGF1 levels, whereas T3/T4 and
T3/reverse-T3 ratios were positively correlated with total IGF1. In
conclusion, a polymorphism that results in a decreased DIO1 activity is
associated with an increase in free IGF1 levels. The association of DIO1
haplotype allele 2 with serum T3 levels in the elderly population
suggested a relative increase in its contribution to circulating T3 in
old age.
References:
1. Berry, M. J.; Banu, L.; Larsen, P. R.: Type I iodothyronine deiodinase
is a selenocysteine-containing enzyme. Nature 349: 438-440, 1991.
2. Berry, M. J.; Grieco, D.; Taylor, B. A.; Maia, A. L.; Kieffer,
J. D.; Beamer, W.; Glover, E.; Poland, A.; Larsen, P. R.: Physiological
and genetic analyses of inbred mouse strains with a type I iodothyronine
5-prime deiodinase deficiency. J. Clin. Invest. 92: 1517-1528, 1993.
3. de Jong, F. J.; Peeters, R. P.; den Heijer, T.; van der Deure,
W. M.; Hofman, A.; Uitterlinden, A. G.; Visser, T. J.; Breteler, M.
M. B.: The association of polymorphisms in the type 1 and 2 deiodinase
genes with circulating thyroid hormone parameters and atrophy of the
medial temporal lobe. J. Clin. Endocr. Metab. 92: 636-640, 2007.
4. Hatfield, D.; Diamond, A.: UGA: a split personality in the universal
genetic code. (Letter) Trends Genet. 9: 69-70, 1993.
5. Jakobs, T. C.; Koehler, M. R.; Schmutzler, C.; Glaser, F.; Schmid,
M.; Kohrle, J.: Structure of the human type I iodothyronine 5-prime-deiodinase
gene and localization to chromosome 1p32-p33. Genomics 42: 361-363,
1997.
6. Jansen, M.; Krenning, E. P.; Oostdijik, W.; Docter, R.; Kingma,
B. E.; Van den Brande, J. V. L.; Hennemann, G.: Hyperthyroxinaemia
due to decreased peripheral triiodothyronine production. Lancet 320:
849-851, 1982. Note: Originally Volume II.
7. Kleinhaus, N.; Faber, J.; Kahana, L.; Schneer, J.; Scheinfeld,
M.: Euthyroid hyperthyroxinemia due to a generalized 5-prime-deiodinase
defect. J. Clin. Endocr. Metab. 66: 684-688, 1988.
8. Maia, A. L.; Berry, M. J.; Sabbag, R.; Harney, J. W.; Larsen, P.
R.: Structural and functional differences in the dio1 gene in mice
with inherited type 1 deiodinase deficiency. Molec. Endocr. 9: 969-980,
1995.
9. Mandel, S. J.; Berry, M. J.; Kieffer, J. D.; Harney, J. W.; Warne,
R. L.; Larsen, P. R.: Cloning and in vitro expression of the human
selenoprotein, type I iodothyronine deiodinase. J. Clin. Endocr.
Metab. 75: 1133-1139, 1992.
10. Peeters, R. P.; van den Beld, A. W.; van Toor, H.; Uitterlinden,
A. G.; Janssen, J. A. M. J. L.; Lamberts, S. W. J.; Visser, T. J.
: A polymorphism in type I deiodinase is associated with circulating
free insulin-like growth factor I levels and body composition in humans. J.
Clin. Endocr. Metab. 90: 256-263, 2005.
11. Peeters, R. P.; van Toor, H.; Klootwijk, W.; de Rijke, Y. B.;
Kuiper, G. G. J. M.; Uitterlinden, A. G.; Visser, T. J.: Polymorphisms
in thyroid hormone pathway genes are associated with plasma TSH and
iodothyronine levels in healthy subjects. J. Clin. Endocr. Metab. 88:
2880-2888, 2003.
12. Toyoda, N.; Kleinhaus, N.; Larsen, P. R.: The structure of the
coding and 5-prime flanking region of the type 1 iodothyronine deiodinase
(dio1) gene is normal in a patient with suspected congenital dio1
deficiency. J. Clin. Endocr. Metab. 81: 2121-2124, 1996.
Clinical Synopsis:
Endocrine:
Asymptomatic hyperthyroxinemia
Neck:
Small diffuse goiter
Lab:
Type I iodothyronine deiodinase defect;
Elevated serum thyroxine;
Normal serum triiodothyronine
Inheritance:
Autosomal dominant
Contributors:
John A. Phillips, III - updated: 12/19/2007
John A. Phillips, III - updated: 10/31/2005
John A. Phillips, III - updated: 8/25/2003
Carol A. Bocchini - updated: 6/12/1999
Mark H. Paalman - updated: 9/6/1996
Creation Date:
Victor A. McKusick: 4/4/1991
Edit Dates:
terry: 01/27/2009
carol: 12/19/2007
alopez: 10/31/2005
joanna: 3/17/2004
alopez: 8/25/2003
terry: 6/14/1999
carol: 6/12/1999
carol: 5/2/1998
mark: 3/7/1997
mark: 10/11/1996
terry: 9/19/1996
mark: 9/6/1996
mark: 11/2/1995
carol: 1/17/1995
mimadm: 11/5/1994
carol: 10/18/1993
carol: 8/18/1992
supermim: 3/16/1992
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