Substrate for Thyroid Hormone Synthesis: Biochemistry, Evolution, and Physiology

release to the bloodstream as well as intrathyroidal iodide recycling. Humans bearing mutations impairing any steps leading to thyroglobulin iodination present with congenital hypothyroidism; nevertheless, untreated goitrous patients bearing bi-allelic mutation in thyroglobulin can still make thyroid hormone. Even as thyrocytes in such patients grow to form a goiter, many thyrocytes die in the setting of persistent thyroidal endoplasmic reticulum (ER) stress. Recently, mice with genetic deletion of thyroglobulin have been found to also exhibit net goiter growth but also substantial thyroid cell death despite the complete absence of thyroidal ER stress. These findings suggest the possibility of a surprising back-up mechanism in both patients and mouse models bearing bi-allelic thyroglobulin mutation, that can link the iodination machinery for thyroid hormone synthesis to thyroid cell death.