Missense mutation (C1263R) in the thyroglobulin gene causes congenital goiter with mild hypothyroidism by impaired intracellular transport.

Metabolic abnormalities in thyroid hormonogenesis cause congenital goiter. Here we studied a case of mild hypothyroidism caused by a novel missense mutation in the thyroglobulin (TG) gene. A female patient underwent thyroidectomy twice at the age of 27 and 43 years because of gradual enlargement of the thyroid. By RNase cleavage assay and PCR direct sequencing we identified a thymine to cytosine transition at nucleotide 3828 (from the transcription start site) which causes amino acid change from cysteine to arginine at codon 1263. A pedigree study suggested autosomal recessive inheritance due to consanguineous marriage of her parents. Immunohistochemical study suggested impaired intracellular transport of the mutant TG. Sensitivity to endoglycosidase H confirmed that the mutant TG failed to reach the Golgi compartment. Native polyacrylamide 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 after translation. To examine if the mutant TG is functionally defective, we separated thyroid tissue extract on a Biogel A5m column and measured T4 and T3 released from proteins in each fraction by treatment with proteinase K. Although thyroid hormones released per mole of the mutant 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 premature degradation by "quality control" mechanisms. Although the tissue TG content was greatly reduced, the hypothyroidism was mild with slow progression of the goiter, because the mutant TG was a relatively good substrate for the synthesis of the thyroid hormones.