Genetic Influences on Thyroid Function Tests

  • Wendy M. van der Deure
  • Marco Medici
  • Robin P. Peeters
  • Theo J. Visser
Chapter
Part of the Thyroid Function Testing book series (ENDO, volume 28)

Abstract

In this review we will discuss the possible effects of polymorphic variation in the genes important for thyroid hormone synthesis, metabolism, and action, on the interindividual variation in thyroid functions tests. The genes involved are summarized in the following outline of thyroid hormone production and action, but their role is discussed in detail in other sections (Chaps. 1 and 4). In addition to these genes, we will also briefly discuss the possible contribution of genetic variation in the thyroid-specific transcription factors which are known to be important for thyroid development and regulation: TTF1, TTF2, and Pax8.

Keywords

Fatigue Iodine Adenoma Cortisol Iodide 

References

  1. 1.
    Björkman U, Elkholm R. Biochemistry of thyroid hormone formation and secretion. In: Greer MA, ed. The Thyroid Gland. New York, NY: Raven Press; 1990:83-126.Google Scholar
  2. 2.
    Larsen PR, Davies TE, Hay ID. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, Larsen RR, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, PA: WB Saunders; 1998:389-515.Google Scholar
  3. 3.
    Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87:1068-1072.PubMedCrossRefGoogle Scholar
  4. 4.
    Hansen PS, Brix TH, Sorensen TI, Kyvik KO, Hegedus L. Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab. 2004;89:1181-1187.PubMedCrossRefGoogle Scholar
  5. 5.
    Samollow PB, Perez G, Kammerer CM, et al. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab. 2004;89:3276-3284.PubMedCrossRefGoogle Scholar
  6. 6.
    Panicker V, Wilson SG, Spector TD, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol (Oxford). 2008;68:652-659.CrossRefGoogle Scholar
  7. 7.
    Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH. Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program. J Pediatr. 1986;109:959-964.PubMedCrossRefGoogle Scholar
  8. 8.
    Katakami H, Kato Y, Inada M, Imura H. Hypothalamic hypothyroidism due to isolated thyrotropin-releasing hormone (TRH) deficiency. J Endocrinol Invest. 1984;7:231-233.PubMedGoogle Scholar
  9. 9.
    Niimi H, Inomata H, Sasaki N, Nakajima H. Congenital isolated thyrotrophin releasing hormone deficiency. Arch Dis Child. 1982;57:877-878.PubMedCrossRefGoogle Scholar
  10. 10.
    Collu R, Tang J, Castagne J, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab. 1997;82:1561-1565.PubMedCrossRefGoogle Scholar
  11. 11.
    Bonomi M, Busnelli M, Beck-Peccoz P, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009;360:731-734.PubMedCrossRefGoogle Scholar
  12. 12.
    Hayashizaki Y, Hiraoka Y, Tatsumi K, et al. Deoxyribonucleic acid analyses of five families with familial inherited thyroid stimulating hormone deficiency. J Clin Endocrinol Metab. 1990;71:792-796.PubMedCrossRefGoogle Scholar
  13. 13.
    Biebermann H, Liesenkotter KP, Emeis M, Oblanden M, Gruters A. Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene. Pediatr Res. 1999;46:170-173.PubMedCrossRefGoogle Scholar
  14. 14.
    Pohlenz J, Dumitrescu A, Aumann U, et al. Congenital secondary hypothyroidism caused by exon skipping due to a homozygous donor splice site mutation in the TSHbeta-subunit gene. J Clin Endocrinol Metab. 2002;87:336-339.PubMedCrossRefGoogle Scholar
  15. 15.
    Krohn K, Paschke R. Somatic mutations in thyroid nodular disease. Mol Genet Metab. 2002;75:202-208.PubMedCrossRefGoogle Scholar
  16. 16.
    Duprez L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet. 1994;7:396-401.PubMedCrossRefGoogle Scholar
  17. 17.
    Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest. 1997;99:3018-3024.PubMedCrossRefGoogle Scholar
  18. 18.
    Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S.Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med. 1995;332:155-160.PubMedCrossRefGoogle Scholar
  19. 19.
    Dechairo BM, Zabaneh D, Collins J, et al. Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur J Hum Genet. 2005;13:1223-1230.PubMedCrossRefGoogle Scholar
  20. 20.
    Brand OJ, Barrett JC, Simmonds MJ, et al. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Hum Mol Genet. 2009;18:1704-1713.PubMedCrossRefGoogle Scholar
  21. 21.
    Tomer Y, Barbesino G, Keddache M, Greenberg DA, Davies TF. Mapping of a major susceptibility locus for Graves' disease (GD-1) to chromosome 14q31. J Clin Endocrinol Metab. 1997;82:1645-1648.PubMedCrossRefGoogle Scholar
  22. 22.
    van der Deure WM, Uitterlinden AG, Hofman A, et al. Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam study. Clin Endocrinol (Oxford). 2008;68:175-181.Google Scholar
  23. 23.
    Peeters RP, van Toor H, Klootwijk W, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab. 2003;88:2880-2888.PubMedCrossRefGoogle Scholar
  24. 24.
    Hansen PS, van der Deure WM, Peeters RP, et al. The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population. Clin Endocrinol (Oxford). 2007;66:827-832.CrossRefGoogle Scholar
  25. 25.
    Gabriel EM, Bergert ER, Grant CS, van Heerden JA, Thompson GB, Morris JC. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab. 1999;84:3328-3335.PubMedCrossRefGoogle Scholar
  26. 26.
    Nogueira CR, Kopp P, Arseven OK, Santos CL, Jameson JL, Medeiros-Neto G. Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil. Thyroid. 1999;9:1063-1068.PubMedCrossRefGoogle Scholar
  27. 27.
    Sykiotis GP, Neumann S, Georgopoulos NA, et al. Functional significance of the thyrotropin receptor germline polymorphism D727E. Biochem Biophys Res Commun. 2003;301:1051-1056.PubMedCrossRefGoogle Scholar
  28. 28.
    Dechairo BM, Zabaneh D, Collins J, et al. Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur J Hum Genet. 2005;13(11):1223-1230.PubMedCrossRefGoogle Scholar
  29. 29.
    Pasca di Magliano M, Di Lauro R, Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc Natl AcadSci U S A. 2000;97:13144-13149.CrossRefGoogle Scholar
  30. 30.
    Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet. 1998;19:87-90.PubMedCrossRefGoogle Scholar
  31. 31.
    Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. 1998;19:83-86.PubMedCrossRefGoogle Scholar
  32. 32.
    Torban E, Pelletier J, Goodyer P. F329L polymorphism in the human PAX8 gene. Am J Med Genet. 1997;72:186-187.PubMedCrossRefGoogle Scholar
  33. 33.
    Kimura S, Hara Y, Pineau T, et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10:60-69.PubMedCrossRefGoogle Scholar
  34. 34.
    Breedveld GJ, van Dongen JW, Danesino C, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet. 2002;11:971-979.PubMedCrossRefGoogle Scholar
  35. 35.
    Krude H, Schutz B, Biebermann H, et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest. 2002;109:475-480.PubMedGoogle Scholar
  36. 36.
    Pohlenz J, Dumitrescu A, Zundel D, et al. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest. 2002;109:469-473.PubMedGoogle Scholar
  37. 37.
    Gudmundsson J, Sulem P, Gudbjartsson DF, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet. 2009;41:460-464.PubMedCrossRefGoogle Scholar
  38. 38.
    De Felice M, Ovitt C, Biffali E, et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet. 1998;19:395-398.PubMedCrossRefGoogle Scholar
  39. 39.
    Bamforth JS, Hughes IA, Lazarus JH, Weaver CM, Harper PS. Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet. 1989;26:49-51.PubMedCrossRefGoogle Scholar
  40. 40.
    Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet. 1998;19:399-401.PubMedCrossRefGoogle Scholar
  41. 41.
    Carre A, Castanet M, Sura-Trueba S, et al. Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. Hum Genet. 2007;122:467-476.PubMedCrossRefGoogle Scholar
  42. 42.
    Tonacchera M, Banco M, Lapi P, et al. Genetic analysis of TTF-2 gene in children with congenital hypothyroidism and cleft palate, congenital hypothyroidism, or isolated cleft palate. Thyroid. 2004;14:584-588.PubMedCrossRefGoogle Scholar
  43. 43.
    Venza M, Visalli M, Venza I, et al. Altered binding of MYF-5 to FOXE1 promoter in non-syndromic and CHARGE-associated cleft palate. J Oral Pathol Med. 2009;38:18-23.PubMedCrossRefGoogle Scholar
  44. 44.
    Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature. 1996;379:458-460.PubMedCrossRefGoogle Scholar
  45. 45.
    Eskandari S, Loo DD, Dai G, Levy O, Wright EM, Carrasco N. Thyroid Na+/I symporter. Mechanism, stoichiometry, and specificity. J Bioll Chem. 1997;272:27230-27238.CrossRefGoogle Scholar
  46. 46.
    Nicola JP, Basquin C, Portulano C, Reyna-Neyra A, Paroder M, Carrasco N. The Na+/I symporter mediates active iodide uptake in the intestine. Am J Physiol. 2009;296:C654-C662.CrossRefGoogle Scholar
  47. 47.
    Wapnir IL, Goris M, Yudd A, et al. The Na+/I symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid. Clin Cancer Res. 2004;10:4294-4302.PubMedCrossRefGoogle Scholar
  48. 48.
    Bizhanova A, Kopp P. Minireview: the sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology. 2009;150:1084-1090.PubMedCrossRefGoogle Scholar
  49. 49.
    Kopp P, Pesce L, Solis SJ. Pendred syndrome and iodide transport in the thyroid. Trends Endocrinol Metab. 2008;19:260-268.PubMedCrossRefGoogle Scholar
  50. 50.
    Azaiez H, Yang T, Prasad S, et al. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet. 2007;122:451-457.PubMedCrossRefGoogle Scholar
  51. 51.
    Wangemann P, Nakaya K, Wu T, et al. Loss of cochlear HCO3 secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol. 2007;292:F1345-F1353.PubMedCrossRefGoogle Scholar
  52. 52.
    van de Graaf SA, Ris-Stalpers C, Pauws E, Mendive FM, Targovnik HM, de Vijlder JJ. Up to date with human thyroglobulin. J Endocrinol. 2001;170:307-321.PubMedCrossRefGoogle Scholar
  53. 53.
    Rivolta CM, Targovnik HM. Molecular advances in thyroglobulin disorders. Clin Chim Acta. 2006;374:8-24.PubMedCrossRefGoogle Scholar
  54. 54.
    Kim PS, Hossain SA, Park YN, Lee I, Yoo SE, Arvan P. A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog/cog mouse: a model of human endoplasmic reticulum storage diseases. Proc Natl Acad Sci U S A. 1998;95:9909-9913.PubMedCrossRefGoogle Scholar
  55. 55.
    Gough S. The thyroglobulin gene: the third locus for autoimmune thyroid disease or a false dawn? Trends Mol Med. 2004;10:302-305.PubMedCrossRefGoogle Scholar
  56. 56.
    Tomer Y, Huber A. The etiology of autoimmune thyroid disease: a story of genes and environment. J Autoimmun. 2009;32:231-239.PubMedCrossRefGoogle Scholar
  57. 57.
    De Deken X, Wang D, Many MC, et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem. 2000;275:23227-23233.PubMedCrossRefGoogle Scholar
  58. 58.
    Grasberger H, Refetoff S. Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent. J Biol Chem. 2006;281:18269-18272.PubMedCrossRefGoogle Scholar
  59. 59.
    Moreno JC, Bikker H, Kempers MJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med. 2002;347:95-102.PubMedCrossRefGoogle Scholar
  60. 60.
    Moreno JC, Visser TJ. New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr Dev. 2007;10:99-117.PubMedCrossRefGoogle Scholar
  61. 61.
    Zamproni I, Grasberger H, Cortinovis F, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab. 2008;93:605-610.PubMedCrossRefGoogle Scholar
  62. 62.
    Taurog A. Molecular evolution of thyroid peroxidase. Biochimie. 1999;81:557-562.PubMedCrossRefGoogle Scholar
  63. 63.
    Bakker B, Bikker H, Vulsma T, de Randamie JS, Wiedijk BM, De Vijlder JJ. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab. 2000;85:3708-3712.PubMedCrossRefGoogle Scholar
  64. 64.
    Bikker H, Baas F, De Vijlder JJ. Molecular analysis of mutated thyroid peroxidase detected in patients with total iodide organification defects. J Clin Endocrinol Metab. 1997;82:649-653.PubMedCrossRefGoogle Scholar
  65. 65.
    Gnidehou S, Caillou B, Talbot M, et al. Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB J. 2004;18:1574-1576.PubMedGoogle Scholar
  66. 66.
    Moreno JC. Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression. Horm Res. 2003;60(suppl 3):96-102.PubMedCrossRefGoogle Scholar
  67. 67.
    Friedman JE, Watson JA Jr, Lam DW, Rokita SE. Iodotyrosine deiodinase is the first mammalian member of the NADH oxidase/flavin reductase superfamily. J Biol Chem. 2006;281:2812-2819.PubMedCrossRefGoogle Scholar
  68. 68.
    Moreno JC, Klootwijk W, van Toor H, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med. 2006;358:1811-1818.CrossRefGoogle Scholar
  69. 69.
    Afink G, Kulik W, Overmars H, et al. Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism. J Clin Endocrinol Metab. 2006;93:4894-4901.CrossRefGoogle Scholar
  70. 70.
    Cheng SY. Multiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors. Rev Endocr Metab Disord. 2000;1:9-18.PubMedCrossRefGoogle Scholar
  71. 71.
    Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev. 2001;81:1097-1142.PubMedGoogle Scholar
  72. 72.
    Olateju TO, Vanderpump MP. Thyroid hormone resistance. Ann Clin Biochem. 2006;43:431-440.PubMedCrossRefGoogle Scholar
  73. 73.
    Yen PM. Molecular basis of resistance to thyroid hormone. Trends Endocrinol Metab. 2003;14:327-333.PubMedCrossRefGoogle Scholar
  74. 74.
    Weiss RE, Refetoff S. Resistance to thyroid hormone. Rev Endocr Metab Disord. 2000;1:97-108.PubMedCrossRefGoogle Scholar
  75. 75.
    Sorensen HG, van der Deure WM, Hansen PS, et al. Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes. Thyroid. 2008;18:1087-1094.PubMedCrossRefGoogle Scholar
  76. 76.
    Tinnikov A, Nordstrom K, Thoren P, et al. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. Embo J. 2002;21:5079-5087.PubMedCrossRefGoogle Scholar
  77. 77.
    Venero C, Guadano-Ferraz A, Herrero AI, et al. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev. 2005;19:2152-2163.PubMedCrossRefGoogle Scholar
  78. 78.
    Kaneshige M, Suzuki H, Kaneshige K, et al. A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci U S A. 2002;98:15095-15100.CrossRefGoogle Scholar
  79. 79.
    Liu YY, Schultz JJ, Brent GA. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem. 2003;278:38913-38920.PubMedCrossRefGoogle Scholar
  80. 80.
    Robbins J, Bartalena L. Plasma transport of thyroid hormone. In: Hennemann G, ed. Thyroid Hormone Metabolism. New York, NY: Marcel Dekker; 1986:3-38.Google Scholar
  81. 81.
    Hennemann G, Visser TJ. Thyroid hormone synthesis, plasma membrane transport and metabolism. In: Grossman A, ed. Handbook of Experimental Pharmacology. Berlin, Germany: Springer; 1997:75-117.Google Scholar
  82. 82.
    Hennemann G, Docter R. Plasma transport proteins and their role in tissue delivery of thyroid hormone. In: Greer MA, ed. The Thyroid Gland. New York, NY: Raven Press; 1990:221-232.Google Scholar
  83. 83.
    Mannavola D, Vannucchi G, Fugazzola L, et al. TBG deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature. J Mol Med. 1990;84:864-871.CrossRefGoogle Scholar
  84. 84.
    Refetoff S. Inherited thyroxine-binding globulin abnormalities in man. Endocr Rev. 1989;10:275-293.PubMedCrossRefGoogle Scholar
  85. 85.
    Mori Y, Jing P, Kayama M, et al. Gene amplification as a common cause of inherited thyroxine-binding globulin excess: analysis of one familial and two sporadic cases. Endocr J. 1999;46:613-619.PubMedCrossRefGoogle Scholar
  86. 86.
    Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum Mutat. 2001;17:493-503.PubMedCrossRefGoogle Scholar
  87. 87.
    Moses AC, Rosen HN, Moller DE, et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. 2001;86:2025-2033.CrossRefGoogle Scholar
  88. 88.
    Cameron SJ, Hagedorn JC, Sokoll LJ, Caturegli P, Ladenson PW. Dysprealbuminemic hyperthyroxinemia in a patient with hyperthyroid graves disease. Clin Chem. 2001;51:1065-1069.CrossRefGoogle Scholar
  89. 89.
    Bartalena L, Robbins J. Variations in thyroid hormone transport proteins and their clinical implications. Thyroid. 1992;2:237-245.PubMedCrossRefGoogle Scholar
  90. 90.
    Hennemann G, Docter R, Krenning EP, Bos G, Otten M, Visser TJ. Raised total thyroxine and free thyroxine index but normal free thyroxine. A serum abnormality due to inherited increased affinity of iodothyronines for serum binding protein. Lancet. 1979;1:639-642.PubMedCrossRefGoogle Scholar
  91. 91.
    Pannain S, Feldman M, Eiholzer U, Weiss RE, Scherberg NH, Refetoff S. Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine. J Clin Endocrinol Metab. 2000;85:2786-2792.PubMedCrossRefGoogle Scholar
  92. 92.
    Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev. 2001;22:451-476.PubMedCrossRefGoogle Scholar
  93. 93.
    Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem. 2003;278:40128-40135.PubMedCrossRefGoogle Scholar
  94. 94.
    Friesema EC, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet. 2004;364:1435-1437.PubMedCrossRefGoogle Scholar
  95. 95.
    Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet. 2004;74:168-175.PubMedCrossRefGoogle Scholar
  96. 96.
    Dominguez-Gerpe LF-IM, Vieitez-Rodriguez O, Areal-Mendez C, Eiras-Martinez A, San-Jose E, Lado-Abeal J. Study of a possible association between serum levels of T4, T3 or TSH and the SNP S33P of the monocarboxylate transporter 8 (MCT8). Thyroid. 2006;16:883-884, 878.Google Scholar
  97. 97.
    van der Deure WM, Peeters RP, Visser TJ. Genetic variation in thyroid hormone transporters. Best Pract Res Clin Endocrinol Metab. 2007;21:339-350.PubMedCrossRefGoogle Scholar
  98. 98.
    Lago-Leston R, Iglesias MJ, San-Jose E, et al. Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of Northwest Spain (Galicia). Clin Endocrinology. 2009;70(4):636-643.Google Scholar
  99. 99.
    Kim DK, Kanai Y, Matsuo H, et al. The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics. 2002;79:95-103.PubMedCrossRefGoogle Scholar
  100. 100.
    Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol. 2008;22:1357-1369.PubMedCrossRefGoogle Scholar
  101. 101.
    Heuer H, Maier MK, Iden S, et al. The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone sensitive neuron populations. Endocrinology. 2005;146(4):1701-1706. PubMedCrossRefGoogle Scholar
  102. 102.
    Heuer H, Visser TJ. Minireview: pathophysiological importance of thyroid hormone transporters. Endocrinology. 2009;150:1078-1083.PubMedCrossRefGoogle Scholar
  103. 103.
    Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology. 2006;147:4036-4043.PubMedCrossRefGoogle Scholar
  104. 104.
    Konig J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol. 2006;372:432-443.PubMedCrossRefGoogle Scholar
  105. 105.
    Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001;120:525-533.PubMedCrossRefGoogle Scholar
  106. 106.
    Fujiwara K, Adachi H, Nishio T, et al. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001;142:2005-2012.PubMedCrossRefGoogle Scholar
  107. 107.
    Abe T, Kakyo M, Tokui T, et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem. 1999;274:17159-17163.PubMedCrossRefGoogle Scholar
  108. 108.
    Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ. Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol. 2002;16:2283-2296.PubMedCrossRefGoogle Scholar
  109. 109.
    Mikkaichi T, Suzuki T, Onogawa T, et al. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004;101:3569-3574.PubMedCrossRefGoogle Scholar
  110. 110.
    van der Deure WM, Peeters RP, Visser TJ. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10 and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol. 2010;44(1):1-11.Google Scholar
  111. 111.
    Abe T, Unno M, Onogawa T, et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001;120:1689-1699.PubMedCrossRefGoogle Scholar
  112. 112.
    van der Deure WM, Friesema EC, de Jong FJ, et al. OATP1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology. 2008;149(9):4695-4701.PubMedCrossRefGoogle Scholar
  113. 113.
    Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol. 2005;1:429-445.PubMedCrossRefGoogle Scholar
  114. 114.
    Niemi M, Backman JT, Kajosaari LI, et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther. 2005;77:468-478.PubMedCrossRefGoogle Scholar
  115. 115.
    van der Deure WM, Hansen PS, Peeters RP, et al. Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology. 2008;149:5307-5314.PubMedCrossRefGoogle Scholar
  116. 116.
    Sugiyama D, Kusuhara H, Taniguchi H, et al. Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J Biol Chem. 2003;278:43489-43495.PubMedCrossRefGoogle Scholar
  117. 117.
    van der Deure WM, Appelhof BC, Peeters RP, et al. Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol (Oxford). 2008;69:804-811.CrossRefGoogle Scholar
  118. 118.
    Canani LH, Capp C, Dora JM, et al. The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2005;90:3472-3478.PubMedCrossRefGoogle Scholar
  119. 119.
    Mentuccia D, Proietti-Pannunzi L, Tanner K, et al. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes. 2002;51:880-883.PubMedCrossRefGoogle Scholar
  120. 120.
    Dayan CM, Panicker V. Novel insights into thyroid hormones from the study of common genetic variation. Nat Rev Endocrinol. 2009;5:211-218.PubMedCrossRefGoogle Scholar
  121. 121.
    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002;23:38-89.PubMedCrossRefGoogle Scholar
  122. 122.
    Hernandez A, Martinez ME, Fiering S, Galton VA, St Germain D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest. 2006;116:476-484.PubMedCrossRefGoogle Scholar
  123. 123.
    Hernandez A, Fiering S, Martinez E, Galton VA, St Germain D. The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology. 2002;143:4483-4486.PubMedCrossRefGoogle Scholar
  124. 124.
    Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol. 2001;15:2137-2148.PubMedCrossRefGoogle Scholar
  125. 125.
    Berry MJ, Grieco D, Taylor BA, et al. Physiological and genetic analyses of inbred mouse strains with a type I iodothyronine 5′-deiodinase deficiency. J Clin Invest. 1993;92:1517-1528.PubMedCrossRefGoogle Scholar
  126. 126.
    Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005;37:1247-1252.PubMedCrossRefGoogle Scholar
  127. 127.
    Galton VA, Schneider MJ, Clark AS, St Germain DL. Life without thyroxine to 3,5,3′-triiodothyronine conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology. 2009;150:2957-2963.PubMedCrossRefGoogle Scholar
  128. 128.
    Peeters RP, van der Deure WM, Visser TJ. Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases. Eur J Endocrinol. 2006;155:655-662.PubMedCrossRefGoogle Scholar
  129. 129.
    Panicker V, Cluett C, Shields B, et al. A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J Clin Endocrinol Metab. 2008;93:3075-3081.PubMedCrossRefGoogle Scholar
  130. 130.
    de Jong FJ, Peeters RP, den Heijer T, et al. The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. J Clin Endocrinol Metab. 2007;92:636-640.PubMedCrossRefGoogle Scholar
  131. 131.
    Cooper-Kazaz R, van der Deure WM, Medici M, et al. Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. J Affect Disord. 2009;116:113-116.PubMedCrossRefGoogle Scholar
  132. 132.
    Peeters RP, van den Beld AW, Attalki H, et al. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am J Physiol Endocrinol Metab. 2005;289:E75-E81.PubMedCrossRefGoogle Scholar
  133. 133.
    Panicker V, Wilson SG, Spector TD, et al. Genetic loci linked to pituitary-thyroid axis setpoints: a genome-wide scan of a large twin cohort. J Clin Endocrinol Metab. 2008;93(9):3519-3523.PubMedCrossRefGoogle Scholar
  134. 134.
    Arnaud-Lopez L, Usala G, Ceresini G, et al. Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet. 2008;82:1270-1280.PubMedCrossRefGoogle Scholar
  135. 135.
    van der Deure WM, Hansen PS, Peeters RP, et al. The effect of genetic variation in the type 1 deiodinase gene on the inter-individual variation in serum thyroid hormone levels. An investigation in healthy Danish twins. Clin Endocrinol (Oxford). 2009;70(6):954-960.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Wendy M. van der Deure
  • Marco Medici
  • Robin P. Peeters
  • Theo J. Visser
    • 1
  1. 1.Department of Internal Medicine, Erasmus MCErasmus University Medical SchoolGE RotterdamThe Netherlands

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