Characteristic analysis and therapeutic development in rdw rats with congenital hypothyroidism

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A mutation in the Thyroglobulin (Tg) gene (Tg-G2320R) is the primary cause of hereditary dwarfism and hypothyroidism in the rdw rat.1) Elastase and lipase reduced in pancreatic proteome and those proteins recovered by thyroxine injection or thyroid graft. 2) The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of desease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free chiols, and was associated with activated ER stress response but incomplete ER associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC C13 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Non covalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in paralled with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid, goiter formation in rdw rats. 3) Dopamine D2-like receptor function is converted from excitatory to inhibitory by thyroxine in the developmental hippocampus using rdw rats having deficient thyroid hormone. 4) The infertility of rdw male rats was recovered by thyroid graft.