DEFECTIVE ORGANIFICATION OF IODIDE CAUSING CONGENITAL GOITROUS HYPOTHYROIDISM

A 26-yr-old Japanese woman with congenital goitrous hypo-thyroidism an d sensorineural deafness underwent a thyroidectomy. Examination of the thyroid gland revealed characteristic features of multinodular goiter . The T-3 and T-4 content in thyroglobulin (Tg) were 0.03 and 0.02 mol /mol Tg, respectively. Iodide incorporation into Tg, using slices of t he thyroid tissue, revealed that iodide organification of thyroid tiss ue from our patient was markedly lower than that of normal controls. T hen, guaiacol and iodide oxidation activities of thyroid peroxidase (T PO) in our patient's thyroid tissue were lower than those of normal co ntrols (guaiacol assay: 1.92 vs. 30.0 +/- 5.7 mGU/mg protein; iodide a ssay: 1.1 us. 6.6 +/- 2.8 mIU/mg protein). Lineweaver-Burk plot analys is of the oxidation rates of guaiacol and iodide indicated that this p atient's TPO had a defect in the binding of guaiacol and iodide, but t he coupling activity of the patient's TPO was not decreased compared w ith 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 kil obases 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 det ected only in the TPO gene, but this point mutation does not alter the amino acid residue. It is possible that posttranslational modificatio n such as abnormal glycosylation may occur in the TPO molecules. Furth ermore, it is possible that there are differences in the tertiary stru ctures of the TPO molecules between our patient and normal subjects. T he above abnormalities of TPO molecules may play an important role in our patient's dyshormonogenesis.