A prealbumin variant with an increased affinity for T4 and reverse-T3

Area of Science:

• Endocrinology
• Protein Chemistry
• Molecular Biology

Background:

• Thyroid hormone metabolism involves complex regulation of circulating hormone levels.
• Thyroxine (T4) and triiodothyronine (T3) are key thyroid hormones, with reverse T3 (rT3) being an inactive metabolite.
• Thyroid hormone-binding proteins, primarily albumin, transthyretin (prealbumin), and thyroxine-binding globulin, influence hormone distribution.

Observation:

• A euthyroid female (LC) presented with persistently elevated serum total T4 and rT3, but normal T3 levels.
• Serum concentrations of all known T4-binding proteins were within normal limits.
• A variant prealbumin (prealbumin LC) was identified, showing increased affinity for T4.

Findings:

• Prealbumin LC demonstrated a sevenfold higher affinity constant for T4 binding compared to normal prealbumin.
• The variant prealbumin LC also bound significant amounts of rT3, which is not typically observed with normal prealbumin.
• The T4-binding capacity and molecular characteristics (size, electrophoretic mobility) of prealbumin LC were similar to normal prealbumin, suggesting preserved structure.

Implications:

• The identified prealbumin variant is responsible for the abnormal thyroid hormone levels in LC.
• This finding highlights the role of prealbumin's binding characteristics in regulating circulating thyroid hormone concentrations.
• A hydrophobic amino acid substitution in the prealbumin monomer is postulated to cause the increased affinity for T4 and rT3.