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-T(4). Although her serum TSH normalized, her serum T(4) remained low. Affected family members had low total T(4) and T(3), but a normal free T(4) 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 T(4) and T(3). 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 T(4). CONCLUSIONS: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T(4) resulting in low serum T(4). However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.