Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death

Area of Science:

• Endocrinology
• Cell Biology
• Genetics

Background:

• Thyroxine synthesis is crucial for vertebrate life, occurring in thyroid follicles via thyroglobulin iodination.
• Congenital hypothyroidism due to thyroglobulin mutations causes misfolded protein, ER stress, and impaired secretion.
• Paradoxically, affected individuals survive despite absent thyroglobulin secretion, suggesting an alternative thyroxine source.

Purpose of the Study:

• To investigate the mechanism of thyroxine synthesis in congenital hypothyroidism with absent thyroglobulin ER export.
• To elucidate how affected individuals survive despite severe thyroidal ER stress and cell death.
• To establish the disease mechanism underlying survival in thyroglobulin mutation-induced hypothyroidism.

Main Methods:

• Studied humans, mice, and rats with biallelic thyroglobulin mutations (TGW2346R/W2346R, TGcog/cog, TGrdw/rdw).
• Assessed thyroglobulin ER export, thyroidal ER stress, and cell death.
• Investigated thyroxine synthesis and survival mechanisms in TGrdw/rdw rats, including response to antithyroid drugs and aging effects.

Main Results:

• Mutant thyroglobulin failed ER export, causing severe thyroidal ER stress and cell death in all models.
• Thyroxine was synthesized and measurable, even after antithyroid drug treatment proved lethal in TGrdw/rdw rats.
• Thyroxine synthesis occurred on mutant thyroglobulin within dead thyrocytes, which were iodinated and consumed by live thyrocytes, supporting survival and goiter growth.

Conclusions:

• Dead thyrocytes provide a compensatory mechanism for thyroxine synthesis and organismal survival in congenital hypothyroidism.
• This novel disease mechanism highlights the role of cellular decomposition and recycling in maintaining essential hormone levels.
• Progressive failure of goiter growth with aging leads to profound hypothyroidism, indicating the limits of this compensatory survival strategy.