ABSTRACT Efficient generation of the thyroid hormone thyroxine (T4) requires the iodination of thyroglobulin (Tg), which is synthesized in the endoplasmic reticulum (ER) and undergoes folding and trafficking to the thyroid follicle lumen wherein iodination takes place. Endogenous T4 is 100% produced by thyrocytes, and the formation of T4 in Tg has been conserved in evolution for ≥ 500 million years. To date, hundreds of different pathogenic mutations of the TG gene have been found to cause congenital hypothyroidism in humans. Genetic hypothyroidism from homozygous (or compound heterozygous) TG mutation is rare, but the frequency of a single pathogenic TG allele in the human population is very common (≥ 1:200 individuals). All Tg mutants studied to date are misfolded proteins trapped in the ER, causing ER stress. We recently reported that in untreated TG homozygotes, endogenous thyroid hormone synthesis still occurs despite failure of Tg export from the ER. The mechanism involves thyroid epithelial cell death, with extrusion of dead thyrocytes into the lumen of thyroid follicles, leading to the disintegration and iodination of those cells in the follicle lumen. Massive expression of Tg protein in thyrocytes, and the extremely high frequency of heterozygous TG mutations in the population, now leads us to ask whether thyroid epithelial cell death may also be a (heretofore unsuspected) widespread feature across individuals who are simple heterozygotes for mutant TG. This can be easily tested in animal models. Additionally, in homozygous rdw/rdw (Tg-G2298R) rats, thyroid cell death has long been recognized as a factor blocking goiter growth. Remarkably, we now find that in the congenital goiter mouse (cog/cog, Tg-L2263P), there is also widespread thyroid cell death (that is nevertheless outpaced by thyroid growth). In the current proposal, 1) we have engineered a rdw/rdw knockin mouse and will directly compare cell growth and cell death to that seen in cog/cog mice. 2) W