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Genetics and phenomics of hypothyroidism and goiter due to TPO mutations

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Abstract

Thyroid peroxidase (TPO) is a heme binding protein localized on the apical membrane of the thyrocyte. TPO enzymatic activity is essential for thyroid hormonogenesis. Inactivating mutations form the molecular basis for a specific subtype of congenital hypothyroidism: thyroid dyshormonogenesis due to an iodide organification defect. The most common phenotype of this autosomal recessive disease is a total iodide organification defect, with severe and permanent hypothyroidism as a consequence. Currently 61 properly annotated mutations in the TPO gene have been reported, of which the majority are missense mutations. Functional data of most missense mutations is not available, making it necessary to revert to in silico methods for functional interpretation of mutations.

We hypothesize that iodine status is the main phenomic modifier of TPO function.

Section snippets

The function of TPO in thyroid physiology

Thyroid peroxidase or thyroperoxidase (TPO) (OMIM 606765) is a glycosylated membrane bound hemoprotein localized on the apical membrane of the thyrocyte where it plays an essential role in the process of thyroid hormone synthesis.

The thyrocytes that surround the follicular lumen are the thyroid hormone forming units within the thyroid gland. Fig. 1 (top part) represents a schematically drawn thyrocyte, highlighting the main proteins essential to thyroid hormone synthesis, with special focus on

The TPO gene, mRNA, and protein

The TPO enzymatic activity has been described decades ago, and already at that time TPO was linked to the most frequent type of hereditary thyroid hormone synthesis defects (DeGroot and Niepomniszcze, 1977).

Several groups reported the complete sequence of the human TPO coding region; a major full-length transcript consisting of 3048 nucleotides encoding 933 amino acids (GenBank accession number NM_000547.4) and a minor transcript lacking 171 nucleotides (Kimura et al., 1987, Libert et al., 1987

The role of TPO in hypothyroidism

Congenital hypothyroidism is the most common endocrine disease, affecting 1 in every 1200 newborns in the Netherlands (Vulsma and de Vijlder, 2002).

Defects in the process of thyroid hormone synthesis account for about 15% of all cases of permanent congenital hypothyroidism in the Netherlands (de Vijlder et al., 1997). If untreated, hypothyroidism due to dyshormonogenesis leads to increased TSH secretion, thyroid stimulation, and goiter in an attempt to compensate for the diminished capacity of

The phenomics of TPO mutations

Iodine is the main environmental factor interacting with TPO.

Excess iodide is known to acutely inhibit thyroid hormone synthesis in case of normally functioning thyroid gland (The Wolff–Chaikoff effect) (Wolff and Chaikoff, 1948). The proposed mechanism is that excess iodide leads to the formation of 2-iodohexadecanal that inhibits H2O2 generation thereby inhibiting the TPO catalyzed iodination (Panneels et al., 1994).

One patient who presented with congenital hypothyroidism was diagnosed as

Conclusion

Activity of the glycosylated membrane bound hemoprotein TPO is essential for thyroid hormone synthesis at the apical membrane of the thyrocyte. Whether TPO is involved only in the iodination of tyrosine residues or also in the coupling of iodinated tyrosine residues to thyroid hormone, is a matter of dispute.

Inactivating mutations in TPO are the main cause for autosomal recessive iodide organification defects, with currently 61 properly annotated mutations reported. It is temping to speculate

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