Table of Contents - *601038
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Genome
DNA
Protein
Gene Info
Variation
Animal Models
Cellular Pathways
| *601038 | |||||||||||||||
| DEIODINASE, IODOTHYRONINE, TYPE III; DIO3 | |||||||||||||||
| Alternative titles; symbols | |||||||||||||||
| THYROXINE DEIODINASE, TYPE III; TXDI3 IODOTHYRONINE DEIODINASE, PLACENTAL TYPE | |||||||||||||||
| HGNC Approved Gene Symbol: DIO3 | |||||||||||||||
| Cytogenetic location: 14q32.31 Genomic coordinates (GRCh37): 14:102,027,687 - 102,029,788 (from NCBI) | |||||||||||||||
| TEXT | |||||||||||||||
| Cloning | |||||||||||||||
| Thyroid hormone is critical to the normal development of the human central nervous system. Salvatore et al. (1995) noted that, despite the presence of thyroxine (T4) and thyroid follicles in the fetal thyroid by 10 to 12 weeks of gestation, as well as the potential availability of maternal thyroid hormone, the free concentration of the active thyroid hormone T3 is less than half that of maternal levels up to the time of delivery. The physiologic rationale for this circumstance is not well understood, but the authors suggested that it is possible that 'normal' circulating T3 concentrations could have deleterious effects on immature tissues or could enhance the metabolic requirements of the fetus. There are 2 principal mechanisms by which the circulating fetal T3 concentration is maintained at low levels. One is that the type I iodothyronine deiodinase (147892) in fetal liver is expressed at lower levels relative to those in adult life. This reduces the extra thyroidal T3 supply from this source. The second important factor in maintaining low serum T3 concentrations is the expression of high levels of the type III deiodinase in placenta of all species examined. Type III iodothyronine deiodinase catalyzes the conversion of T4 and T3 to inactive metabolites. Salvatore et al. (1995) cloned human placental type III iodothyronine deiodinase (which they referred to as D3). It is a selenoenzyme, as evidenced by (1) the presence of an in-frame UGA codon at position 144; (2) the synthesis of a 32-kD (75)Se-labeled protein in D3 cDNA transfected cells; and (3) the presence of a selenocysteine insertion sequence element in the 3-prime untranslated region of an mRNA that is required for its expression. The authors stated that the D3 selenocysteine insertion sequence element is more potent than that found in the type I deiodinase or glutathione peroxidase (138320) gene, suggesting a high priority for selenocysteine incorporation into this enzyme. The conservation of this enzyme from Xenopus laevis tadpoles to humans implies an essential role for regulation of thyroid hormone inactivation during embryologic development. By Northern blot analysis, Hernandez et al. (2004) detected several DIO3 transcripts. A 2.1-kb transcript was highly expressed in placenta, fetal liver, and uterus, and a 3.2-kb transcript predominated in testis, bladder, and uterus. A 4.8-kb transcript was detected in heart and skeletal muscle, but it hybridized only with the most 5-prime region of the DIO3 cDNA, suggesting that it is not a true coding transcript. Some or all of these transcripts were also present in adrenal cortex, thyroid, prostate, stomach, pancreas, and fetal lung. | |||||||||||||||
| Gene Function | |||||||||||||||
| Huang et al. (2000) reported the case of a 3-month-old infant with massive hepatic hemangiomas and primary hypothyroidism who needed very high doses of thyroid hormone to restore euthyroidism and normal thyrotropin secretion. This finding suggested that the rate of degradation of thyroid hormone was accelerated. They subsequently identified high levels of type III iodothyronine deiodinase activity in the hemangioma tissue. Normally present in the brain and placenta, this selenoenzyme catalyzes the conversion of thyroxine to reverse triiodothyronine and the conversion of triiodothyronine to 3,3-prime-diiodothyronine, both of which are biologically inactive. They then retrospectively analyzed other patients with hemangiomas and identified additional patients with similar histories and other hemangiomas with type III iodothyronine deiodinase activity. | |||||||||||||||
| Gene Structure | |||||||||||||||
| Hernandez et al. (2004) determined that, like the mouse Dio3 gene, the coding region and 3-prime UTR of human DIO3 are contained within a single exon. In both mouse and human, the promoter elements are located immediately upstream and are extremely GC rich (80% of the sequence). | |||||||||||||||
| Mapping | |||||||||||||||
| By FISH, Hernandez et al. (1998) mapped the human DIO3 gene to 14q32 and the mouse Dio3 gene to 12F1. See also DIO1 (147892) and DIO2 (601413). Hernandez et al. (2004) noted that mouse Dio3 is imprinted and preferentially expressed from the paternal allele during fetal development. They determined that exon 1 of the DIO3OS gene (608523), which is transcribed in the opposite orientation of the DIO3 gene, maps to a region 1 kb upstream of the DIO3 transcription start site and within the DIO3 GC-rich promoter region. | |||||||||||||||
| Animal Model | |||||||||||||||
| By targeted inactivation of the Dio3 gene in mouse embryonic stem cells, Hernandez et al. (2006) generated Dio3-knockout mice, which demonstrated neonatal thyrotoxicosis followed later by persistent central hypothyroidism. Early in life, the mutant mice had delayed T3 clearance, markedly elevated serum T3 levels, and overexpression of T3-inducible genes in the brain. From postnatal day 15 to adulthood, Dio3-knockout mice exhibited central hypothyroidism, with low serum levels of T4 and T3, and modest or no increase in TSH (see 118850) concentration; peripheral tissues were also hypothyroid. Hypothalamic T3 was decreased, whereas thyrotropin-releasing hormone (TRH; 613879) expression was elevated. Hernandez et al. (2006) concluded DIO3 plays a critical role in the maturation and function of the thyroid axis. | |||||||||||||||
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