In humans, deficient thyroglobulin (Tg, the thyroid prohormone) is an important cause of congenital hypothyroid goiter; further, homozygous mice expressing two cog~ cog alleles (linked to the Tg locus) exhibit the same phenotype. Tg mutations might affect multiple different steps in thyroid hormone synthesis; however, the microscopic and biochemical phenotype tends to involve enlargement of the thyroid ER and accumulation of protein bands of Mr< 100. To explore further the cell biology of this autosomal recessive illness, we have examined the folding and intracellular transport of newly synthesized Tg in cog/cog thyroid tissue. We find that mutant mice synthesize a fulllength Tg, which appears to undergo normal N-linked glycosylation and glucose trimming. Nevertheless, in the mutant, Tg is deficient in the folding that leads to homodimerization, and there is a deficiency in the quantity of intracellular Tg transported to the distal portion of the secretory pathway. Indeed, we find that the underlying disorder in cog~ cog mice is a thyroid ER storage disease, in which a temperature-sensitive Tg folding defect, in conjunction with normal ER quality control mechanisms, leads to defective Tg export. In relation to quality control, we find that the physiological response in this illness includes the specific induction of five molecular chaperones in the thyroid ER. Based on the pattern of chaperone binding, different potential roles for individual chaperones are suggested in glycoprotein folding, retention, and degradation in this ER storage disease.

EFICIENT thyroglobulin (Tg) 1 is estimated to cause congenital goiter and hypothyroidism with a prevalence of~'~ 1/40,000 humans, and similar pathology has been described in numerous animal models (Medeiros-Neto et al., 1993; Medeiros-Neto and Stanbury, 1994). Affected individuals may exhibit a range of phenotypes, including hypothyroid growth retardation, abnormal central nervous system function, and local compression of neck tissues due to an enlarged thyroid mass. In mice, a defective cog gene accounts for the development of the same autosomal recessive phenotypes (Beamer et al., 1987; Sugisaki et al., 1992); the cog gene is linked to the Tg locus (Taylor and Rowe, 1987) and appears to represent a mutation in the Tg gene product (Adkison et al., 1990).