Defective organification of iodide causing congenital goitrous hypothyroidism.

A 26-yr-old Japanese woman with congenital goitrous hypo-thyroidism and sensorineural deafness underwent a thyroidectomy. Examination of the thyroid gland revealed characteristic features of multinodular goiter. The T3 and T4 content in thyroglobulin (Tg) were 0.03 and 0.02 mol/mol Tg, respectively. Iodide incorporation into Tg, using slices of the thyroid tissue, revealed that iodide organification of thyroid tissue from our patient was markedly lower than that of normal controls. Then, guaiacol and iodide oxidation activities of thyroid peroxidase (TPO) in our patient's thyroid tissue were lower than those of normal controls (guaiacol assay: 1.92 vs. 30.0 +/- 5.7 mGU/mg protein; iodide assay: 1.1 vs. 6.6 +/- 2.8 mIU/mg protein). Lineweaver-Burk plot analysis of the oxidation rates of guaiacol and iodide indicated that this patient's TPO had a defect in the binding of guaiacol and iodide, but the coupling activity of the patient's TPO was not decreased compared with those of two normal thyroids. In this case and in control subjects, Nothern gel analysis of TPO messenger RNA from unstimulated and TSH-stimulated thyroid cells revealed a 3.2 kilobase species in the former and four distinct messenger RNA species of 4.0, 3.2, 2.1, and 1.7 kilobases in the latter. Western blot analysis of TPOs obtained from this patient and from control subjects identified the same 107 kDa protein, using antimicrosomal antibody-positive serum. We analyzed the coding sequence in the patient's TPO gene by using polymerase chain reaction technique. A single point mutation of G-->C at 1265 base pair was detected only in the TPO gene, but this point mutation does not alter the amino acid residue. It is possible that posttranslational modification such as abnormal glycosylation may occur in the TPO molecules. Furthermore, it is possible that there are differences in the tertiary structures of the TPO molecules between our patient and normal subjects. The above abnormalities of TPO molecules may play an important role in our patient's dyshormonogenesis.