Seven subjects belonging to three families (ME, MA, MO), with congenital goiter and various degrees of thyroid hypofunction, were investigated from the standpoints of clinical, biochemical, and molecular biology. In two of these families (ME, MA), 6 individuals had low serum levels of Tg-related antigens with a minor increase after bovine TSH (bTSH) stimulation. A large proportion of the tracer was incorporated into serum albumin, and Tg antigens in the thyroid extracts were barely detectable by RIA. (0.19 mg/g tissue; normal, 70-90 mg/g). Gel filtration (CL6B Sepharose gel) showed absence of a normal Tg peak, and SDS agarose gel electrophoresis indicated complete absence of Tg dimer and monomer. Immunoelectrophoresis confirmed the absence of Tg-related antigens. Thus, in these patients a quantitative defect of Tg gene expression was characterized. By contrast, in the MO family a high basal serum concentration of immunoreactive Tg was present, with an exaggerated response to bTSH. Thyroid extracts revealed elevated TPO activity and normal levels of Tg-related antigens. Tg was also eluted in the gel filtration columns with the same mobility as standard 19S Tg. Immunoelectrophoresis against rabbit and human Tg was abnormal, with two precipitin arcs being detected. The Tg molecule after hydrolysis yielded only DIT and MIT, with poor formation of iodothyronines. Microscopic studies revealed a pronounced lack of colloid in the follicular lumina, and overdistended endoplasmic reticulum cisternae.(ABSTRACT TRUNCATED AT 250 WORDS)