A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Euthyroid hyperthyroxinemia can be caused by genetic abnormalities in thyroxine-binding proteins.
• Transthyretin (TTR) is a key protein responsible for transporting thyroxine (T4) in the blood.

Purpose of the Study:

• To investigate the genetic basis of euthyroid hyperthyroxinemia in a family with increased T4-TTR association.
• To identify the specific mutation in the TTR gene responsible for the observed phenotype.

Main Methods:

• Polymerase chain reaction (PCR) amplification and sequencing of TTR gene exons.
• Amino acid sequencing of tryptic peptides from purified TTR.
• Restriction digestion analysis using Fnu 4H I enzyme.

Main Results:

• Identified a heterozygous mutation in exon 4 of the TTR gene (threonine 109 substitution).
• The mutation resulted in a TTR molecule with a threefold increased affinity for T4.
• Affected individuals were clinically euthyroid with normal free T4 levels despite elevated total T4.

Conclusions:

• An autosomal dominant mutation in the TTR gene causes euthyroid hyperthyroxinemia by increasing T4 binding affinity.
• The threonine 109 substitution in TTR is responsible for the inherited abnormality in thyroxine transport.