Thyroid Dysfunction: Molecular Genetics


The thyroid produces thyroxine (T4) and triiodothyronine (T3). A surplus or a deficit in thyroid hormone production, due to thyroid dysfunction, results in hyper‐ or hypothyroidism respectively. A spectrum of thyroid‐specific gene mutations, implicit in the control of thyroid function and growth, underline the molecular mechanisms leading to thyroid dysfunction.

Keywords: hyperthyroidism; hypothyroidism; goiter; toxic adenoma; congenital hypothyroidism

Figure 1.

Thyroid dysfunction can involve abnormalities in thyroid hormone production and/or thyroid proliferation. The two conditions are not necessarily linked, for example, hyperthyroidism can be associated with a normal size thyroid gland or a goiter, while hypothyroidism may occur in the presence of a goiter, a normal size gland or thyroid hypoplasia/agenesis.

Figure 2.

Diagram of a thyroid epithelial cell showing the steps of thyroid hormone production (thyroxine (T4) and triiodothyronine (T3)) comprising iodide (I) uptake from the blood, iodide transport across the thyroid cell into the follicular lumen, iodide oxidation and coupling (organification), storage of thyroid hormones bound to thyroglobulin (TG) as the ‘colloid’ and lastly TG endocytosis and release of thyroid hormone into the blood. Disturbance of genes involved in thyroid hormone synthesis (SLC5A5, SLC26A4 (pendrin), TPO, TG, DUOX2) usually results in a goiter with euthyroid or hypothyroid function. Depending on their nature, mutations in thyroid‐stimulating hormone receptor (TSHR), which is the key regulator of both thyroid function and growth, cause either hyperthyroidism and goiter or hypothyroidism in a normal or hypoplastic gland. In contrast, defects in transcription factors regulating thyroid differentiation (PDS, FOXE1, PAX8) result in hypothyroidism and a variable degree of thyroid hypoplasia. (Note putative function of pendrin as the basal iodide transporter.) MIT: mono‐iodotyrosine; DIT: di‐iodotyrosine.



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Further Reading

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Kosugi S, Inoue S, Matsuda A and Jhiang SM (1998) Novel, missense and loss of function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. Journal of Clinical Endocrinology and Metabolism 83: 3373–3376.

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Rodien P, Bremont C, RaffinSanson ML, et al. (1998) Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. New England Journal of Medicine 339: 1823–1826.

Targovnik HM, MedeirosNeto G, Varela V, et al. (1993) A nonsense mutation causes human hereditary congenital goitre with preferential generation of a 171 nucleotide deleted thyroglobulin ribonucleic acid messenger. Journal of Clinical Endocrinology and Metabolism 77: 210–215.

Web Links

Genew Human Gene Nomenclature Database. HUGO approved nomenclature and links to further information‐bin/nomenclature/

NCBI Entrez nucleotides database. Use GenBank ID number in search engine for further information

NCBI OMIM: Online Mendelian Inheritance in Man. An online a catalog of human genes and genetic disorders (use OMIM number to search)

TSH Receptor Database II. The TSHR mutation database is aimed at scientists and clinicians. It comprises all TSHR mutations reported up to December 2002 and contains all available functional and clinical data on the different TSHR mutations including 55 pedigrees of patients with germline TSHR mutations with detailed information on molecular aspects, clinical courses and treatment options. In addition, a first compilation of site‐directed mutagenesis studies has been included as well as special search tools and an administrator tool for submission of novel TSHR mutations. The TSHR mutation database is installed as one of the locus specific HUGO mutation databases (∼cotton/dblist.htm). It is listed under index TSHR 603372 (http://;∼cotton/glsdbq.htm) and can be accessed via www.uni‐

Dual oxidase 2 (DUOX2); Locus ID: 50506. LocusLink:

Thyroid peroxidase (TPO); Locus ID: 7173. LocusLink:

Thyroglobulin (TG); Locus ID: 7038. LocusLink:

Thyroid stimulating hormone receptor (TSHR); Locus ID: 7253. LocusLink:

Thyroid transcription factor 1 (PDS); Locus ID: 7080. LocusLink:

Dual oxidase 2 (DUOX2); MIM number: 606759. OMIM:‐post/Omim/dispmim?606759

Thyroid peroxidase (TPO); MIM number: 606765. OMIM:‐post/Omim/dispmim?606765

Thyroglobulin (TG); MIM number: 188450. OMIM:‐post/Omim/dispmim?188450

Thyroid stimulating hormone receptor (TSHR); MIM number: 603372. OMIM:‐post/Omim/dispmim?603372

Thyroid transcription factor 1 (PDS); MIM number: 600635. OMIM:‐post/Omim/dispmim?600635

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Ludgate, Marian, and Fuhrer, Dagmar(Jan 2006) Thyroid Dysfunction: Molecular Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0006176]