ReviewGenetics and phenomics of hypothyroidism and goiter due to TPO mutations
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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2021, Molecular and Cellular EndocrinologyCitation Excerpt :Congenital hypothyroidism (CH) is a complex group of thyroid diseases which results from alteration in the biosynthesis of thyroid hormones (dyshormonogenesis, 15–20% of cases) or in thyroid gland development (grouped under the name of thyroid dysembryogenesis or dysgenesis, 80–85% of cases). Dyshormonogenesis has been associated to variants in the SLC5A [Spitzweg and Morris, 2010; Targovnik et al., 2017, 2020], SLC26A4 [Bizhanova and Kopp, 2010; Targovnik et al., 2020; Wémeau and Kopp, 2017], SLC26A7 [Bruellman et al., 2020b, Cangul, et al., 2018, Hermanns et al., 2020; Ishii et al., 2019; Zou et al., 2018], thyroid peroxidase (TPO) [Abramowicz et al., 1992; Ris-Stalpers and Bikker, 2010; Targovnik et al., 2017, 2020], DUOX1 [Aycan et al., 2017; Bruellman et al., 2020b, Liu et al., 2019; Watanabe et al., 2019; Zou et al., 2018], DUOXA1 [Liu et al., 2019], DUOX2 [Belforte et al., 2016; Grasberger, 2010; Moreno et al., 2002; Muzza et al., 2014; Muzza and Fugazzola, 2017; Park et al., 2016; Targovnik et al., 2020], DUOXA2 [Muzza and Fugazzola, 2017], iodotyrosine deiodinase (IYD) [Moreno and Visser, 2010; Targovnik et al., 2017] and thyroglobulin (TG) [Citterio et al., 2019; Di Jeso and Arvan, 2016; Ieiri et al., 1991; Targovnik et al., 2010a, 2011, 2016, 2017, 2020] genes. Thyroid dyshormonogenesis due to TG gene variants have an estimated incidence of approximately 1 in 100,000 newborns.
Biochemical and molecular evaluation of thyroid gland disorders in children
2021, Biochemical and Molecular Basis of Pediatric DiseaseThe TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism
2020, Molecular and Cellular Endocrinology