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

• Published in: European thyroid journal 2017-01, Vol.6 (3), p.138-142
• Main Authors: Pappa, Theodora, Moeller, Lars C., Edidin, Deborah V., Pannain, Silvana, Refetoff, Samuel
• Format: Article
• Language: English
• Subjects: Translational Thyroidology / Original Paper
• ISSN: 2235-0640; 2235-0802
• DOI: 10.1159/000455097

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.