Low Levels of Thyroglobulin Messenger Ribonucleic Acid in Congenital Goitrous Hypothyroidism with Defective Thyroglobulin Synthesis*

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Abstract
We characterized the virtual absence of immunoassayable thyroglobulin (Tg) in the serum and thyroid gland of two siblings (MA, JNA) and one nephew (RSS) from a family without inbreeding or familial goiter. Diagnosis of defective Tg gene expression was based on findings of normal PBI and low serum T4, low or normal serum T3, negative perchlorate discharge test, and virtual absence of the serum Tg response to challenge by bovine TSH. This conclusion was confirmed by analysis of proteins in the goiter extracts. Only minute amounts of immunoassayable Tg were detected by RIA (MA, 0.11; JNA, 0.19 mg/g tissue; compared to 70-90 mg/g in normal thyroid tissue). Gel filtration in Sephacryl S300 showed the absence of a normal Tg peak at 280 nm and concentration of label mostly on albumin. A minor intermediate peak of radioactivity was also detected, with the size of, approximately normal Tg. Sodium dodecyl sulfate-agarose gel electrophoresis indicated the absence of Tg dimer and monomer, and Western blotting and immunoelectrophoresis confirmed this finding. Dot blot quantification of Tg and thyroid peroxidase mRNA indicated decreased hybridization of the patients'' mRNA (MA, 44%; JNA, 63%) with phTgM2 (Tg probe) and increased hybridization (MA, 191%; JNA, 182%) with the pM5 (thyroid peroxidase probe) compared with control thyroid tissue. Dot blot analysis of Tg mRNA from the two siblings weakly hybridized with 3'' and 5'' Tg probes. RNA analysis by means of Northern transfer showed a clear signal of hybridization with Tg probe (phTgM1) in the 8- to 9-kilobase range, corresponding to the normal size Tg mRNA. No major polymorphisms were noted in Southern blotting, using seven restriction endonucleases. We conclude that no gross alteration of the 5'' region of Tg gene was present in these patients. Ultrastructural examination of the thyroid tissue indicated that the rough endoplasmic reticulum was not augmented, nor were the cisternae of rough endoplasmic reticulum dilated. The defect observed in these goiters is diminished tissue concentration of Tg mRNA with defective translation. However, small amounts of functionally active Tg could be synthesized, iodinated, and immediately hydrolized, yielding mostly T3, owing to the intense tissue stimulation by TSH.