A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families

Abstract

Background: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD).

Objective: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago.

Methods: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T₄. Although her serum TSH normalized, her serum T₄ remained low. Affected family members had low total T₄ and T₃, but a normal free T₄ index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T₄ and T₃. His brother had a similar thyroid phenotype.

Results: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T₄.

Conclusions: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T₄ resulting in low serum T₄. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

Keywords: Mutation; T4-binding affinity; Thyroxine-binding globulin; Thyroxine-binding globulin deficiency.

Fig. 1

a Pedigree of family 1: TFT results are aligned with each symbol representing a family member. Abnormally high values are in red and low values in blue (colors refer to the online version only). The arrow denotes the proband. Filled symbols are affected hemizygous and half-filled symbols are heterozygous. b Pedigree of family 2, presented in the same way as family 1. The serum TBG concentrations for the probands of families 1 and 2 are in the text. c Sequencing chromatograms corresponding to a normal individual and a hemizygous and heterozygous individual with the V215G TBG variant. d IEF gel showing the TBG isoform patterns in serum from a hemizygous and a heterozygous patient compared to a normal family member, a normal control (TBG-N), a pregnant individual and an individual on estrogens. TPO, thyroperoxidase.