Alternative titles; symbols
HGNC Approved Gene Symbol: IYD
SNOMEDCT: 17885001;
Cytogenetic location: 6q25.1 Genomic coordinates (GRCh38): 6:150,369,012-150,405,969 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.1 | Thyroid dyshormonogenesis 4 | 274800 | Autosomal recessive | 3 |
IYD facilitates iodide salvage in thyroid by catalyzing deiodination of mono- and diiodotyrosine, the halogenated byproducts of thyroid hormone production (Friedman et al., 2006).
By database analysis, Gnidehou et al. (2004) identified a human thyroid cDNA encoding IYD, which they designated DEHAL1. The deduced 289-amino acid protein has a calculated molecular mass of 33 kD and contains a conserved nitroreductase domain. Northern blot analysis detected highest expression of a 7-kb DEHAL1 transcript in thyroid, with lower expression in kidney and trachea. EST database analysis suggested that DEHAL1 is also expressed in liver and colon. DEHAL1 was expressed in the membrane faction of transfected human embryonic kidney cells. Immunohistochemical analysis of human thyroid showed DEHAL1 diffusely localized in the cytoplasm of most of tall active columnar cells, as well as in flattened inactive thyrocytes. In many cells, DEHAL1 labeling was stronger on the apical membrane.
By database analysis, Friedman et al. (2006) identified human IYD and several mammalian orthologs. The deduced proteins contain an N-terminal membrane anchor, an intermediate domain that shows highest sequence variability among species, and a conserved C-terminal domain that resembles enzymes of the bacterial NADH oxidase/flavin reductase superfamily.
Gnidehou et al. (2004) determined that the IYD gene contains 5 exons.
By genomic sequence analysis, Gnidehou et al. (2004) mapped the IYD gene to chromosome 6q24-q25.
Gnidehou et al. (2004) showed that DEHAL1 catalyzed NADPH-dependent deiodination of mono- and diiodotyrosine, with greater activity against monoiodotyrosine.
In 4 patients from 3 unrelated consanguineous families with hypothyroidism and biochemical features or a clinical history suggestive of an iodotyrosine deiodinase defect (TDH4; 274800), Moreno et al. (2008) identified homozygosity for 3 different mutations in the IYD gene (612025.0001-612025.0003, respectively). The mutations were not found in 118 control chromosomes. Functional studies showed that the mutations disrupt the capacity of DEHAL1 to deiodinate either of its natural substrates, monoiodotyrosine and diiodotyrosine.
In an affected mother and daughter from a consanguineous Belgian Moroccan family segregating apparently recessive hypothyroidism and goiter consistent with deiodinase deficiency (TDH4; 274800), Afink et al. (2008) identified homozygosity for a 658G-A transition in exon 4 of the IYD gene, resulting in an ala220-to-thr (A220T) substitution (612025.0004) within the enzymatic dehalogenase domain. Functional characterization showed that the mutation completely abolished dehalogenase enzymatic activity. Heterozygosity for the mutation was found in 4 offspring who were clinically euthyroid and nongoitrous at the time of DNA testing; however, 6 years later, a heterozygous 14-year-old son developed goiter and hypothyroidism, indicating dominant inheritance with incomplete penetrance. The 658G-A variant was also found in 1 of 100 control alleles, suggesting that it might represent a functional SNP.
In a 26-year-old mentally retarded woman, born in Germany to consanguineous parents of Turkish origin, who presented at 18 months of age with primary hypothyroidism, goiter, and an elevated diiodotyrosine level (TDH4; 274800), Moreno et al. (2008) identified homozygosity for a 301C-T transition in exon 2 of the IYD gene, resulting in an arg101-to-trp (R101W) substitution at the tenth position of the catalytic nitroreductase domain of the DEHAL1 protein between 2 predicted flavin mononucleotide-binding amino acids. The parents were euthyroid and had no goiter. The mutation was not found in 118 control chromosomes. Functional studies in mammalian cells revealed that the mutation virtually abolished the capacity of DEHAL1 to deiodinate mono- and diiodotyrosine.
In 2 sisters with hypothyroidism diagnosed in infancy and goiter (TDH4; 274800), born of first-cousin parents who were members of a group of Scottish traveling families previously described by Hutchison and McGirr (1954, 1956), Moreno et al. (2008) identified homozygosity for an in-frame 3-bp deletion (315delCAT) in exon 2 of the IYD gene, resulting in the replacement of both phe105 and ile106 by a leucine residue at position 105 within the nitroreductase domain near a putative flavin mononucleotide-binding amino acid. The mutation was not found in 118 control chromosomes. Functional studies in mammalian cells revealed that the mutation virtually abolished the capacity of DEHAL1 to deiodinate mono- and diiodotyrosine.
In a 9-year-old boy born in France to first-cousin parents of Moroccan descent, who was diagnosed with nonautoimmune hypothyroidism and goiter at age 8 years and had an elevated serum diiodotyrosine level (TDH4; 274800), Moreno et al. (2008) identified homozygosity for a 347T-C transition in exon 2 of the IYD gene, resulting in an ile116-to-thr (I116T) substitution in the nitroreductase domain of DEHAL1 but outside the flavin mononucleotide-binding pocket. The parents were euthyroid and had no goiter. The mutation was not found in 118 control chromosomes. Functional studies in mammalian cells revealed that the mutation markedly reduced the capacity of DEHAL1 to deiodinate mono- and diiodotyrosine, although there was some residual activity (4% and 2.5%, respectively).
In an affected mother and daughter from a consanguineous Belgian Moroccan family segregating apparently recessive hypothyroidism and goiter consistent with deiodinase deficiency (TDH4; 274800), Afink et al. (2008) identified homozygosity for a 658G-A transition in exon 4 of the IYD gene, resulting in an ala220-to-thr (A220T) substitution within the enzymatic dehalogenase domain. Functional characterization showed that the mutation completely abolishes dehalogenase enzymatic activity. Heterozygosity for the mutation was found in 4 offspring who were clinically euthyroid and nongoitrous at the time of DNA testing; however, 6 years later, a heterozygous 14-year-old son developed goiter and hypothyroidism, indicating dominant inheritance with incomplete penetrance. The 658G-A variant was also found in 1 of 100 control alleles, suggesting that it might represent a functional SNP.
Afink, G., Kulik, W., Overmars, H., de Randamie, J., Veenboer, T., van Cruchten, A., Craen, M., Ris-Stalpers, C. Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism. J. Clin. Endocr. Metab. 93: 4894-4901, 2008. [PubMed: 18765512] [Full Text: https://doi.org/10.1210/jc.2008-0865]
Friedman, J. E., Watson, J. A., Jr., Lam, D. W.-H., Rokita, S. E. Iodotyrosine deiodinase is the first mammalian member of the NADH oxidase/flavin reductase superfamily. J. Biol. Chem. 281: 2812-2819, 2006. [PubMed: 16316988] [Full Text: https://doi.org/10.1074/jbc.M510365200]
Gnidehou, S., Caillou, B., Talbot, M., Ohayon, R., Kaniewski, J., Noel-Hudson, M.-S., Morand, S., Agnangji, D., Sezan, A., Courtin, F., Virion, A., Dupuy, C. Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB J. 18: 1574-1576, 2004. Note: Full Article Online. [PubMed: 15289438] [Full Text: https://doi.org/10.1096/fj.04-2023fje]
Hutchison, J. H., McGirr, E. M. Hypothyroidism as an inborn error of metabolism. J. Clin. Endocr. Metab. 14: 869-886, 1954. [PubMed: 13183981] [Full Text: https://doi.org/10.1210/jcem-14-8-869]
Hutchison, J. H., McGirr, E. M. Sporadic non-endemic goitrous cretinism. Hereditary transmission. Lancet 267: 1035-1037, 1956. Note: Originally Volume 1.
Moreno, J. C., Klootwijk, W., van Toor, H., Pinto, G., D'Alessandro, M., Leger, A., Goudie, D., Polak, M., Gruters, A., Visser, T. J. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. New Eng. J. Med. 358: 1811-1818, 2008. [PubMed: 18434651] [Full Text: https://doi.org/10.1056/NEJMoa0706819]