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Thyroxine binding by human transthyretin variants: mutations at position 119, but not position 54, increase thyroxine
A J Curtis1, B J Scrimshaw, D J Topliss
1Ewen Downie Metabolic Unit, Alfred Hospital, Melbourne, Victoria, Australia.
The Journal of Clinical Endocrinology and Metabolism
|February 1, 1994
Summary
The transthyretin (TTR) Met119 mutation doubles T4 binding affinity without changing capacity, explaining elevated hormone levels. Other TTR mutations may not affect T4 binding.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- The transthyretin (TTR) protein transports thyroid hormones.
- A specific mutation, TTRMet119, alters the T4 binding channel.
- Previous studies indicated increased hormone carriage by TTRMet119 variants.
Purpose of the Study:
- To investigate whether the TTRMet119 mutation affects T4 binding affinity or capacity.
- To compare the binding characteristics of TTRMet119 with normal TTR and another variant, TTRGly54.
Main Methods:
- Partial purification of TTR from normal and TTRMet119 individuals using Blue Sepharose chromatography.
- Measurement of T4 binding affinity (Ka) and capacity using purified TTR.
- Comparison of T4 binding with TTRMet119 and TTRGly54 variants.
Main Results:
- Normal TTR bound T4 with intermediate affinity (Ka, 1.63 x 10(7) L/mol).
- TTRMet119 exhibited doubled T4 affinity (Ka, 3.40 x 10(7) L/mol) with no change in binding capacity.
- TTRMet119 showed a 5-fold increase in rT3 binding; TTRGly54 had unchanged T4 affinity.
Conclusions:
- The TTRMet119 mutation increases T4 binding affinity, explaining elevated serum T4 levels.
- TTR gene mutation location influences T4 binding characteristics.
- TTRMet119 represents a specific genetic alteration impacting thyroid hormone transport.