| +147892 | ||||||||||||||||||||||||||||||||||||
| DEIODINASE, IODOTHYRONINE, TYPE I; DIO1 | ||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||
| THYROXINE DEIODINASE, TYPE I; TXDI1 | ||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||
| HYPERTHYROXINEMIA DUE TO DECREASED PERIPHERAL CONVERSION OF T4, INCLUDED | ||||||||||||||||||||||||||||||||||||
| 5-PRIME-DEIODINASE DEFICIENCY, GENERALIZED, CAUSING EUTHYROID HYPERTHYROXINEMIA, INCLUDED | ||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: DIO1 | ||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 1p32.3 Genomic coordinates (GRCh37): 1:54,359,860 - 54,376,758 (from NCBI) | ||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||
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| 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. | ||||||||||||||||||||||||||||||||||||
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