DIO3 is the gene responsible for the deiodinase type 3 (Dio3 or D3) involved in thyroid hormone catabolism, and it plays a role in the maintenance of the hypothalamic–pituitary–thyroid axis. It is one of three diodinase genes, the other two being DIO1 and DIO2. UniProt explains that it is "Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into RT3 (3,3',5'-triiodothyronine) and of T3 (3,5,3'-triiodothyronine) into T2 (3,3'-diiodothyronine). RT3 and T2 are inactive metabolites. [D3] may play a role in preventing premature exposure of developing fetal tissues to adult levels of thyroid hormones."
Research has shown that genetic polymorphisms are less important than alterations in expression of DIO3 that are observed in some pathological conditions.
[PMID 18815314] Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. A 2008 article abstract stated "The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules". Therefore, "In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults." (Abstract)
[PMID 22498139] A 2013 article "Genomic imprinting of the type 3 thyroid hormone deiodinase gene: Regulation and developmental implications" explained that "most tissues express some form of thyroid hormone receptor and, thus, are a target for thyroid hormones." As a result, changes in expression of DIO3 have potential to have significant effects on human health. In their review, they discovered "To date, no direct mutations on the D3 gene with functional consequences have been reported in humans"; however, symptoms and pathological conditions may be caused by "misexpression of the imprinted genes." DIO3 genes are unique: "a puzzling observation about the D3 gene (Dio3) is that it is subject to genomic imprinting, an epigenetic phenomenon affecting a small number of genes that results in the preferential expression of one of the alleles. This characteristic sets the D3 apart from other determinants of thyroid hormone action, and raises the possibility that the epigenetic mechanisms governing the allelic expression of Dio3 are an important determinant of thyroid hormone levels in tissues, and are critical to ensure normal development and physiology." They found in previous research that "In certain models of injury and inflammation, D3 expression can also be induced in tissues and cell types which would not normally express D3 in healthy conditions. This type of D3 induction has been found in the heart when subjected to physiological insults such as myocardial infarction and pulmonary hypertension. Induction of local D3 has also been observed in infiltrating cells during lung infection , after sciatic nerve lesion , and during chronic hind limb inflammation."
[PMID 23586759] A 2013 article "Decreased translation of Dio3 mRNA is associated with drug-induced hepatotoxicity" explained that "human liver, D2 is not expressed, and, as a result, an alternative method of regulation is necessary," namely alteration of D3 expression, to maintain thyroid hormone homoeostasis in the liver. They found "evidence that the translational repression of Dio3 results in less D3 protein, independent of any change in mRNA level, and suggests that the reduced translation is a regulatory mechanism, enabling the liver to combat cellular stress. The known function of Dio3 in modulating thyroxine levels supports further the hypothesis that post-transcriptional regulation may be a rapid compensatory response to drug-induced damage."
[PMID 25040645] A 2014 article called "Defending plasma T3 is a biological priority" explained the mechanism and importance of the enzyme Deiodinase type 3 (D3) in maintaining appropriate levels of T3 in blood plasma in order to prevent hypothyroidism and hyperthyroidism at the cellular level throughout the body. D3 plays a role in preventing thyrotoxicosis from excess T3 in plasma. Overactive D3 enzymes may create a "syndrome of consumptive hypothyroidism, a state of systemic hypothyroidism caused by excessive degradation of T3 and T4 via abnormally high expression of D3." Normally a healthy thyroid gland is able to re-establish appropriate levels of T3 in serum, but a compromised thyroid gland may be unable to assist. Many patients on LT4 monotherapy for primary hypothyroidism generally have lower T3 levels than healthy controls despite normal TSH due to enhanced D3 expression. Regarding the controversy of treating low T3 levels with LT3 medication, the article concludes that more research is necessary, since "The long-term systemic consequences of a relatively low serum T3 are unknown." Regarding some disappointing studies of LT3 therapy, the researchers cautioned that "Many clinical trials comparing monotherapy vs combination therapy might not have been useful, given limitations to normalize serum T3 with a single tablet of liothyronine daily." (NOTE: for more about the LT3 + LT4 combination therapy controversy, see the DIO2 gene page and Hypothyroidism page.)