MISSENSE MUTATION (C1263R) IN THE THYROGLOBULIN GENE CAUSES CONGENITAL GOITER WITH MILD HYPOTHYROIDISM BY IMPAIRED INTRACELLULAR-TRANSPORT

Metabolic abnormalities in thyroid hormonogenesis cause congenital goi ter. Here we studied a case of mild hypothyroidism caused by a novel m issense mutation in the thyroglobulin (TG) gene. A female patient unde rwent thyroidectomy twice at the age of 27 and 43 years because of gra dual enlargement of the thyroid. By RNase cleavage assay and PCR direc t sequencing we identified a thymine to cytosine transition at nucleot ide 3828 (from the transcription start site) which causes amino acid c hange from cysteine to arginine at codon 1263. A pedigree study sugges ted autosomal recessive inheritance due to consanguineous marriage of her parents. Immunohistochemical study suggested impaired intracellula r transport of the mutant TG. Sensitivity to endoglycosidase H confirm ed that the mutant TG failed to reach the Golgi compartment. Native po lyacrylamide gel electrophoresis and Western blot analyses showed that formation of monomers and homodimers was defective with abundant high molecular-weight aggregates which are normally formed transiently aft er translation. To examine if the mutant TG is functionally defective, we separated thyroid tissue extract on a Biogel A5m column and measur ed T4 and T3 released from proteins in each fraction by treatment with proteinase K. Although thyroid hormones released per mole of the muta nt TG protein did not decrease, those released per mg of total protein decreased. In conclusion, the missense mutation in the TG gene caused congenital goiter with mild hypothyroidism due to an altered protein structure which resulted in defective intracellular processing and pre mature degradation by ''quality control'' mechanisms. Although the tis sue TG content was greatly reduced, the hypothyroidism was mild with s low progression of the goiter, because the mutant TG was a relatively good substrate for the synthesis of the thyroid hormones.