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IYD
iodotyrosine deiodinase
IYD is located on the long (q) arm of chromosome 6, at band 6q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
IYD is located on chromosome 6 and encodes iodotyrosine deiodinase, a specialised enzyme expressed predominantly in the thyroid gland. The protein plays a critical role in iodine metabolism by recovering iodine atoms from monoiodotyrosine and diiodotyrosine, which are intermediate compounds produced during thyroid hormone synthesis. This recycling process ensures that the body conserves iodine, a trace element with limited dietary availability that is essential for producing the thyroid hormones thyroxine (T4) and triiodothyronine (T3).
Without functional iodotyrosine deiodinase, iodine bound to tyrosine residues cannot be efficiently salvaged, leading to urinary loss of these compounds and potential iodine deficiency within thyroid cells. The gene's function is particularly relevant in contexts where dietary iodine intake is marginal, as impaired recycling can exacerbate iodine scarcity and compromise thyroid hormone production.
What the gene does
Iodotyrosine deiodinase catalyses the removal of iodine from monoiodotyrosine and diiodotyrosine, two compounds that remain after the thyroid gland cleaves thyroglobulin to release active thyroid hormones. These iodotyrosines are not themselves active hormones but represent valuable iodine reserves that would otherwise be lost if excreted unchanged. The enzyme facilitates the cleavage of the carbon-iodine bond, liberating free iodide ions that can re-enter the thyroid hormone biosynthetic pathway.
The deiodinase operates within thyroid follicular cells, working in coordination with other enzymes involved in thyroid hormone synthesis and regulation. By maintaining an intracellular pool of recycled iodine, the protein reduces the thyroid gland's dependence on circulating iodide derived solely from dietary sources. This salvage mechanism becomes especially important during periods of low iodine availability, helping to sustain thyroid hormone output even when external iodine supply is limited.
The enzyme's activity is tightly regulated to match the metabolic demands of the thyroid gland. Disruption of this recycling process can lead to accumulation of iodotyrosines in serum and urine, a biochemical hallmark of impaired iodotyrosine deiodinase function.
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Chromosome location
The IYD gene is located on the long arm of chromosome 6 at position 6q25.1. This chromosomal region contains several genes involved in metabolic processes. The gene encodes a protein of 289 amino acids, a relatively compact enzyme suited to its specialised catalytic role within thyroid cells.
Protein structure
The iodotyrosine deiodinase protein comprises 289 amino acids. Structural analysis has identified a disordered region spanning amino acids 29 to 69, which may confer flexibility important for substrate recognition or interaction with other cellular components. The presence of intrinsically disordered regions is common in metabolic enzymes and can facilitate conformational changes required for catalytic activity or regulation. Beyond this disordered segment, the protein contains catalytic machinery necessary for cleaving iodine from tyrosine residues, though detailed domain architecture remains an area of ongoing research.
Key variants
Genetic variants in IYD can reduce or eliminate the enzyme's ability to recycle iodine from iodotyrosines. Loss-of-function changes typically result in accumulation of monoiodotyrosine and diiodotyrosine in body fluids, accompanied by increased urinary excretion of these compounds. The clinical consequences of impaired iodotyrosine deiodinase activity depend on dietary iodine intake; individuals with adequate iodine consumption may remain asymptomatic, whereas those with marginal intake may develop thyroid dysfunction. Variant interpretation considers the biochemical phenotype, family history, and population-specific iodine availability.
Sample of pathogenic variants
2 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.658G>A | p.Ala220Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Iodotyrosine deiodination defect |
c.835C>T | p.Arg279Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Iodotyrosine deiodination defect |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in IYD are associated with a form of congenital hypothyroidism characterised by iodine wasting. Affected individuals may present with goitre (thyroid gland enlargement) and varying degrees of thyroid hormone deficiency, particularly in regions where dietary iodine is limited. The condition demonstrates variable expressivity, with some individuals remaining euthyroid (normal thyroid function) if iodine intake is sufficient to compensate for the recycling defect. Early identification and appropriate iodine supplementation can often mitigate thyroid dysfunction, though management must be guided by endocrine specialists to avoid over-supplementation.
No disease links recorded for this gene in our reference set.
UK clinical status
IYD is included on the NHS Genomic Medicine Service panel for congenital hypothyroidism with green (high evidence) classification under pathway R145. This inclusion reflects the gene's established role in thyroid hormone metabolism and the clinical utility of genetic testing in newborns or children presenting with unexplained hypothyroidism or iodine-wasting phenotypes. Identification of IYD variants can inform management strategies, particularly regarding iodine supplementation and long-term endocrine monitoring.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the IYD gene do?
IYD encodes an enzyme that recycles iodine from inactive thyroid hormone precursors, allowing the body to reuse this essential trace element for ongoing thyroid hormone production. This recycling process is especially important when dietary iodine intake is limited.
How is IYD-related thyroid dysfunction inherited?
IYD-related conditions typically follow an autosomal recessive pattern, meaning an individual must inherit altered copies of the gene from both parents to develop significant thyroid dysfunction. Carriers with one altered copy usually maintain normal thyroid function.
Can IYD variants cause problems even with normal iodine intake?
Many individuals with IYD variants remain asymptomatic when dietary iodine is adequate, as sufficient external iodine can compensate for the impaired recycling mechanism. However, clinical expression varies, and some people may still develop mild thyroid abnormalities or goitre even with typical iodine consumption.