Abnormal cellular localization of thyroglobulin mRNA associated with hereditary congenital goiter and thyroglobulin...

The goiters in a breed of hypothyroid goats contain only minute amounts of thyroblobulin-related antigens (0.01% of normal value). We have analyzed these goiters for the presence of mRNA coding for thyroglobulin. Using DNA complementary to beef 33S thyroglobulin mRNA as a probe, we found that the mRNA sequence is present in the goat goiter but at a concentration 1/10-1/40 that of normal goat thyroid. Hybrids of cDNA with either goiter or normal thyroid RNA exhibited identical sharp melting curves which suggests that the same RNA sequence is responsible for hybridization in both tissues. Normal goat thyroid contains a population of large membrane-bound polysomes engaged in throglobulin synthesis. In contrast, such polysomes are absent in the goiter. In regard to subcellular distribution, the relative amount of the thyroglobulin mRNA sequences from the goiter in nuclear RNA was 42% of normal, in cytoplasmic RNA was 7% of normal, and in the membrane fraction was only 1-2% of normal. Our results suggest that the lack of thyroglobulin in these goiters is due to a defect in thyroglobulin mRNA which leads to aberrant processing and/or transport of it from its site of synthesis to the endoplasmic reticulum.