Chapter 56 - Thyroid Peroxidase Deficiency and Total Iodide Organification Defect

Abstract

The iodination of tyrosine residues or iodide organification, is catalyzed by the thyroperoxidase (TPO). TPO is a membrane-bound hemoprotein located at the apical membrane of the thyroid cell. Besides the binding of iodine to tyrosine, TPO also catalyzes the coupling of iodotyrosines to iodothyronine residues in thyroglobulin (Tg) under oxidative conditions. The human TPO gene, which localizes on chromosome 2p25, is divided into 17 exons and covers approximately 150 kilobases (kb) of DNA. Differently sized TPO mRNAs have been recognized in thyroid cells. TPO defects are among the most-frequent cause of inborn abnormalities of thyroid hormone synthesis. Nearly 50 different mutations have been described, mostly single nucleotide substitutions and, in the minority, small deletions/insertions or splicing site mutations. Patients harboring TPO mutations, in compound heterozygosity or homozygosity, present with a TIOD, due to the impaired TPO function, resulting in CH. According to the recessive mode of inheritance, affected subjects are homozygous or compound heterozygous for gene mutations. However, about 20% of the reported families with a TIOD phenotype harbor a single TPO mutated allele. The explanation for TIOD in these single heterozygous cases is presently unknown, except for three cases. The etiological diagnosis of CH, including dyshormonogenic defects due to TPO mutations, is based on clinical examination, biochemical tests, thyroid ultrasound and scintigraphy with KClO4 discharge test. Finally, the severe hypothyroidism resulting from TPO mutations should be promptly treated with the thyroid hormone, in order to maintain TSH levels at the lower limit of the normal range.